Late Sodium Current Blockade in High-Risk ICD Patients
Phase: PHASE3
Conditions: Ischemic Cardiomyopathy, Nonischemic Cardiomyopathy, Heart Failure
Sponsor: University of Rochester

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ClinicalTrials.gov Identifier: NCT01215253 
 
 
 
 
Late Sodium Current Blockade in High-Risk ICD Patients 
 
Ranolazine ICD Trial (RAID) 
 
 
Version 6.0 
September 5, 2014 
 
 
Sponsored by 
University of Rochester 
 
Funding Body 
National Institutes of Health (NIH)/ 
National Heart, Lung & Blood Institute (NHLBI) 
U01 HL96607-01A1 and U01 HL96610-01A1 
 
 
Prinicpal Investigators: 
 
PI: Wojciech Zareba, MD, PhD 
Co-PI: Arthur J. Moss, MD 
 
Co-Investigators 
 David Huang, MD,  
Katia Noyes, PhD,  
University of Rochester Medical Center 
265 Crittenden Blvd,  
Rochester, NY 14642 
 
James Daubert, MD  
Duke University Medical Center 
2301 Erwin Road 
Durham, NC 27710  
 
 
Coordinators  
Suzanne Robertson, PhD, CCRA 
Mary W. Brown, MS 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
A. SPECIFIC AIMS .............................................................................................................................................. 4 
B. BACKGROUND AND SIGNIFICANCE ....................................................................................................... 5 
B.1. Population at High Risk of Cardiac Events ................................................................................................. 5 
B.2. Treatment Options for High-Risk Patients .................................................................................................. 8 
B.3. Late Sodium Currant Blockade ................................................................................................................... 9 
B.4. Significance of the Trial ............................................................................................................................ 10 
C. PRELIMINARY STUDIES ........................................................................................................................... 11 
C.1. Prior Studies Documenting High Risk of Cardiac Events in ICD Patients ............................................... 11 
C.1.1. Secondary Prevention of Mortality .................................................................................................... 11 
C.1.2. Primary Prevention of Mortality in Ischemic Cardiomyopathy ......................................................... 12 
C.1.3. Nonischemic Cardiomyopathy Patients ............................................................................................. 13 
C.2. Ranolazine as Antiarrhythmic Compound (In Vitro Data) ....................................................................... 14 
C.3 Data Regarding Clinical use of Ranolazine ............................................................................................... 17 
C.5. Prior Experience of Investigators .............................................................................................................. 20 
D. RESEARCH DESIGN AND METHODS .................................................................................................... 20 
D.1. Introduction ............................................................................................................................................... 20 
D.2. Specific Aims of the Proposed Trial ......................................................................................................... 20 
D.2.1. Primary aim of the study ................................................................................................................... 20 
D.2.2. Secondary aims of the study .............................................................................................................. 21 
D.3. Overall Design of the Trial ....................................................................................................................... 22 
D.3.1. Device Programming ......................................................................................................................... 24 
D.3.2. In –Person and Telephone Follow-up visits ...................................................................................... 26 
D.4. Study Population: Inclusion and Exclusion Criteria ................................................................................. 27 
D.4.1.Inclusion Criteria ................................................................................................................................ 28 
D.4.2. Exclusion Criteria .............................................................................................................................. 28 
D.4.3. Inclusion of women ........................................................................................................................... 29 
D.5. Follow-up and Endpoints .......................................................................................................................... 29 
D.6. Planned enrollment and randomization ..................................................................................................... 30 
D.7 Timeline of the Study ................................................................................................................................. 30 
D.8. Quality of Life........................................................................................................................................... 30 
D.9. The 6-minute Walk Test (6MWT) ............................................................................................................ 30 
D.10. Blood Samples ........................................................................................................................................ 30 
D.11. TRIAL DESIGN; POWER, DURATION AND STATISTICAL ANALYSIS ...................................... 31 
D.11.1. Endpoint Event Rates ...................................................................................................................... 31 
D.11.2.Significance Level and Power .......................................................................................................... 31 
D.11.3. Recruitment and Randomization ..................................................................................................... 31 
D.11.4. Sequential stopping rule .................................................................................................................. 31 

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D.11.5. Trial Power and Duration@ .............................................................................................................. 33 
D.11.6. Analysis ........................................................................................................................................... 33 
D.11.7. Validation and Assumptions ............................................................................................................ 34 
D.11.8. Sensitivity Analysis ......................................................................................................................... 34 
D.11.9. Treatment Interactions ..................................................................................................................... 34 
D.11.10.Technical Note ................................................................................................................................ 34 
D.11.11. Secondary Analysis ....................................................................................................................... 35 
D.12 ORGANIZATION AND KEY PERSONNEL ........................................................................................ 36 
E. PROTECTION OF HUMAN PATIENTS ................................................................................................... 37 
E.1. Ranolazine ................................................................................................................................................. 37 
E.2. Risk to the Patients .................................................................................................................................... 37 
E.2.1. Adverse Reactions: Clinical Trial Experience ................................................................................... 37 
E.2.2. QT Prolongation ................................................................................................................................. 38 
E.2.3. Drug-drug Interactions ....................................................................................................................... 38 
E.3. Recruitment and Informed Consent ........................................................................................................... 39 
E.4. Protection Against Risk ............................................................................................................................. 39 
E.4.1. ECG monitoring ................................................................................................................................. 39 
E.4.2. Drug interaction ................................................................................................................................. 39 
E.4.3. Implantable Cardioverter Defibrillators ............................................................................................. 39 
E.4.4. Privacy ............................................................................................................................................... 40 
E.5. Data and Safety Monitoring Plan .............................................................................................................. 40 
E.6. Adverse Drug Experience Reporting ......................................................................................................... 40 
E.6.1. Definition of Adverse Drug Experience per 21 CFR 314.80 ............................................................. 40 
E.6.2. Serious Adverse Drug Experience ..................................................................................................... 41 
E.6.3. Unexpected Adverse Drug Experience .............................................................................................. 41 
E.6.4. 15-Day Reporting ............................................................................................................................... 42 
E.7. Discontinuation Criteria/Early Termination .............................................................................................. 42 
E.8. Data Tracking Including Enrollment, Randomization and Withdrawals .................................................. 42 
E.9. Participation of Women and Minorities .................................................................................................... 42 
REFERENCES .................................................................................................................................................... 44 
 
 
 
 
 
 
 
 
 
 
 
 

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A. SPECIFIC AIMS 
Patients with implantable cardioverter-defibrillators (ICDs) who develop ventricular tachyarrhythmias requiring 
appropriate ICD therapy are at significantly increased risk of mortality, recurrent arrhythmias, and 
hospitalization for CHF and other cardiac causes.1-3 There are limited treatment options for patients at high risk 
of 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.4-8 
 
Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells and the late sodium 
current plays a pivotal role in this process.9-14 Sodium overload leads to calcium overload of myocardial cells. 
The consequence of this overload is 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.9,10,13  
 
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.15-18 
Ranolazine is a piperazine derivative with a molecular structure similar to lidocaine. Ranolazine inhibits late 
sodium current without a significant effect on peak sodium current (no QRS changes), and also inhibits IKr, ICa, 
and IKs.16 The IKr blocking effect contributes to minor action potential duration prolongation and QT 
prolongation. However, it does not causes early after depolarizations and ventricular tachyarrhythmias (similarly 
to antiarrhythmic profile of amiodarone) 16. The antiischemic and antiarrhythmic properties of ranolazine might 
decrease the likelihood of arrhythmic events and improve the clinical course of ICD patients. Improvement of 
diastolic myocardial relaxation has been observed with ranolazine in preclinical conditions, heart failure 
patients, and in LQT3 patients.13,19,20 Diabetic patients have shown improvement in glycemic control on 
ranolazine to further contribute to the beneficial effect of the drug. We propose a double-blind placebo-
controlled clinical trial randomizing high-risk ICD patients who will be treated with ranolazine or placebo in 
addition to optimal medical therapy.  
 
Primary aim of the study is: 
To determine whether ranolazine administration will decrease the likelihood of a composite arrhythmia endpoint 
consisting of ventricular tachycardia or ventricular fibrillation (VT/VF) requiring antitachycardia pacing (ATP), 
ICD shocks, or death; 
 
In addition to the above primary specific aim, there are several secondary aims that will be addressed in this trial 
by utilizing data from detailed records of arrhythmia episodes provided by implanted devices, and 
comprehensive data on hospitalizations during follow-up. 
 
Specific secondary aims are as follows: 
1. to determine whether ranolazine administration will decrease the likelihood of a composite arrhythmia 
endpoint consisting of VT or VF requiring ICD shock or death (while excluding VT/VF requiring just ATP) 
2. to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints 
consisting of hospitalization for cardiac causes (including not only hospitalization for heart failure, but also 
hospitalizations related to cardiac arrhythmias, myocardial infarction or ischemia) or death, whichever 
occurs first.  
3. to determine whether ranolazine administration will decrease the likelihood of a composite secondary 
endpoint consisting of CHF hospitalization or death; 
4. to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac 
causes. 
5. to determine whether ranolazine administration will decrease the likelihood of repeated ICD therapies (not 
just first therapy) 
6. to determine whether ranolazine administration will decrease the likelihood of inappropriate shocks (a 
decrease in episodes of atrial fibrillation triggering inappropriate therapy) evaluating the risk of first and risk 
of repeated inappropriate shocks. 

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7. to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured 
by the 6-minute walk test (6MWT) and in the quality of life measured by the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
8. to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of 
ventricular tachyarrhythmias (including torsade de pointes).   
B. BACKGROUND AND SIGNIFICANCE 
 
B.1. Population at High Risk of Cardiac Events   
Over the last 15 years, several key clinical trials were conducted evaluating strategies to reduce mortality in 
high-risk patients defined based on prior history of cardiac arrest or documented ventricular tachyarrhythmias 
(secondary prevention of mortality) or in patients without history of arrhythmic events but with clinical 
characteristics indicating high risk for arrhythmias and mortality (primary prevention of mortality).21-25 Most of 
these trials showed that ICD therapy reduced mortality more effectively when compared to either amiodarone or 
conventional therapy. As a consequence of these clinical trials, an evidence based medicine is currently being 
practiced with over 100,000 ICDs implanted every year in the US and about 250,000 worldwide. However, as 
documented by these pivotal clinical trials and by reports in independent patients’ cohorts, the long-term 
mortality of patients with ICD devices remains high.21-25 
 
Our MADIT II data analyses1,21 documented that of 720 patients with an ICD, 169 patients received 701 
antiarrhythmic device therapies including antitachycardia pacing or ICD shock for ventricular tachyarrhythmias 
(VT) or ventricular fibrillation (VF). The probability of death 1 year after first therapy for VT or VF was 20%. 
The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for 
termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who 
survived without receiving ICD therapy (Figure 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Kaplan-Meier estimates of probability of survival before and after first appropriate ICD therapy for VT or VF.1 
 
 
Recent data from the SCD-HeFT trial demonstrated that patients with at least one appropriate ICD shock have a 
3-fold higher risk of death than patients with no appropriate shocks (Figure 2).3 One or more appropriate ICD 
shocks were experienced by 182 patients of whom 67 died with median time from shock to death equal to 168 
days, less than 6 months. Kaplan-Meier based survival at 1 year after shock was 77%. Patients in NYHA class II 
had an 84% 1-year survival whereas those in NYHA class III had a 64% 1-year survival.  

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Figure 2. Hazard ratios for the risk of death among patients who survived at least 24 hours after a first ICD shock.3 
 
Survival after shock for ventricular tachycardia was similarly poor to survival after ICD shock for ventricular 
fibrillation.3 
 
These two independent ICD cohorts provide very similar data indicating that patients developing arrhythmic 
events are at very high risk of subsequent arrhythmic events and death. It is worth emphasizing that the majority 
of patients who qualify for ICD therapy do not receive ICDs for a variety of reasons including patients’ hesitant 
to have a device, their preference to rely on pharmacological therapy, sometimes their insufficient knowledge of 
the risk, and frequently physicians’ bias toward non-device management of their patients. Such patients as well 
as those with ICDs at high risk would greatly benefit from a pharmacological therapy reducing risk of 
arrhythmic events and death.  
 
Recent, yet unpublished data from the MADIT-CRT trial demonstrate that patients who received their first 
appropriate ICD therapy for VT/VF have the following risk of VT/VF/Death: 45% at 1 year and 60% at 2 years 
after initial VT/VF episode. The risk was similar in ICD and CRT-D arm of the study. This observation together 
with data from prior studies and trials including AVID and OPTIC indicate that patients with prior history of 
VT/VF have very high risk of subsequent VT/VF/Death.    
 
It is important to emphasize that high-risk patients with ICDs include not only those who already developed 
arrhythmic events (either prior or after implantation) but also a large number of patients without evidence for 
arrhythmic events but with clinical characteristics indicating very high likelihood of developing life-threatening 
ventricular arrhythmias and death. There are numerous publications in the literature indicating that different risk 
stratification methods are able to identify high-risk cohort of patients fulfilling ICD indications. We tested 
numerous clinical and ECG/Holter parameters in the MADIT II patients to risk stratify patients with increased 
risk of cardiac events and arrhythmic events. Among numerous variables of interest, clinical variables including 
age, NYHA class, BUN level, atrial fibrillation and QRS duration were found the most useful and most 
practical. Figure 3, shows the data from the conventional arm of the MADIT II indicating that patients with 
BUN>25 mg/dl have the 2-year mortality of 34% in comparison to patients with BUN≤25 mg/dl with 17% 
mortality. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Survival in the MADIT II patients by the BUN levels (Zareba et al.28). 

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Furthermore yet unpublished analysis of data from MADIT-CRT trial indicate that unselected patients who do 
not have arrhythmic events during first 2 years of the trial still present significant risk of subsequent 
VT/VF/Death: 10% at 3rd year of follow-up and 19% at 4th year follow-up.  
 
Our data from the MADIT-CRT Holter substudy26 also demonstrate that patients with non-sustained VT 
(NSVT) have significantly higher risk for arrhythmic events than patients without NSVT.   
  
 
 
Figure 4. Risk of VT/VF or death in the MADIT CRT patients by presence or absence of NSVT in ischemic and nonischemic 
population.  (Mittal et al.26). 
 
We also recently completed and presented at HRS meeting in May 2013 (Zareba et al. HRS 2013)27 results of a 
Risk Stratification Study in ICD Patients (called M2Risk Study) in which we also found that frequent 
VPBs>500 per 24 hour (or >20/hour on average) in Holter recording indicate increased risk of VT/VF in 
ischemic ICD patients.   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Risk of VT/VF in ischemic ICD patients by presence or absence of frequent >500 VPBs on 24-hour Holter NSVT in 
ischemic ICD patients.  (Zareba et al.27). 
 
Recent analysis of data from the SCD-HeFT (Chen et al. JACC 2013; 61:2161-8) document further that 
presence of NSVT detected on ICD interrogation was associated with a hazard ratio of 3.03 for predicting ICD 
shock or death and with hazard ratio of 4.25 for predicting ICD shock.  

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B.2. Treatment Options for High-Risk Patients 
The ICDs reduce mortality by detecting life-threatening ventricular tachyarrhythmias and delivering therapy in 
form of antitachycardia pacing and/or shocks. Clinical trials demonstrated that a significant reduction of 
mortality by ICDs is achieved on top of optimal medical therapy usually consisting of high use of beta-blockers, 
ACE-inhibitors, and statins.21-25 These commonly used pharmacological treatments aim to decrease adrenergic 
activation, reduce adverse myocardial remodeling, decrease disease progression, decrease myocardial ischemia, 
and reduce vulnerability of plaque rupture, just to name few key mechanisms. Unfortunately, high-risk patients 
with ICDs frequently develop arrhythmic events and signs and symptoms of a progression of underlying disease 
despite this comprehensive pharmacological treatment.1-3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6. Cumulative probability of ICD shock for 3 treatment group in the OPTIC Study.7 
 
The last two decades witnessed several failures of different antiarrhythmic drugs administered to reduce the risk 
of ventricular tachyarrhythmias and death in high-risk patients who nowadays qualify for ICD therapy. However, 
there are ongoing efforts to test existing and novel therapies that aim to decrease risk of arrhythmic events and 
decrease mortality in high-risk patients who usually present with signs and symptoms of heart failure. The 
therapies considered in such high-risk patients might include antiarrhythmic drugs,6,7,29 cardiac 
resynchronization therapy,30-32 or ablation of arrhythmogenic foci in the diseased myocardium.33 Among anti-
arrhythmic drugs used in the high-risk ICD patients, sotalol when compared to placebo was shown to 
significantly reduce risk of ventricular tachyarrhythmia requiring ICD shocks or death by 48%.6 Beta-blockers 
were used in 23-37% of patients in that trial and when analyses were confined only to patients on sotalol versus 
no beta-blockers, reduction in endpoints was not statistically significant. Three other trials,4,5,7 compared sotalol 
with beta-blockers and none of them (despite some trends) was able to demonstrate significant the reduction in 
endpoints; more importantly they showed conflicting results. Therefore sotalol did not gain the status of the drug 
of choice for high-risk patients.  
 
In the OPTIC trial,7 amiodarone in combination with beta-blocker significantly decreased (HR=0.27; p<0.001) 
the risk of arrhythmic events when compared with patients on beta-blocker alone (Figure 6). Amiodarone is 
currently used less and less frequently in high-risk patients due to its side effects. In a study evaluating the long-
term clinical course of patients enrolled in the Canadian Implantable Defibrillator Study,8 82% of patients on 
amiodarone developed side effects and 50% required discontinuation or dose reduction.  Figure 7 from a meta-
analysis of drug trials in ICD patients, shows the high likelihood of discontinuation of antiarrhythmic therapy 
with sotalol and amiodarone.33 
Regarding newer drugs, 34 the SHIELD trial35 showed that azimilide was successful in reducing arrhythmic 
events in high-risk ICD patients. However, when analyses were performed with a combined endpoint of ICD 

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shock or death, hazard ratios were not significant: for 75 mg dose of azimilide 0.91 (95% CI: 0.76-1.10) and for 
125 mg dose of azimilide 0.90 (95% CI: 0.74-1.09). The azimilide administration in high-risk patients was 
recently studied in the SHIELD II trial and in April 2013 the trial was stopped by the sponsor presumably for 
financial reasons although no formal statement was presented to date. Recently published trial with the new 
promising compound dronedarone, 29 showed increased mortality in heart failure patients assigned to this drug in 
comparison to placebo.  
 
The SMASH-VT (Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia) trial33 
showed that patients randomized to substrate-based catheter ablation of arrhythmogenic ventricular foci had 
appropriate ICD shocks reduced from 33% to 15%. Although very promising and requiring confirmation in a 
larger trial, this invasive strategy could only be implemented in highly specialized centers that limit its 
widespread application.    
 
Based on the above evidence, the majority of high-risk patients are still managed mostly with beta-blockers and 
sometimes with amiodarone with all its limitations.      
 
 
Figure 7. Discontinuation of the therapy for any reason in studies comparing Class III antiarrhythmics with beta-blockers.33 
 
B.3. Late Sodium Currant Blockade  
Ion channels mediating the peak sodium current responsible for depolarization of myocardial cells are activated 
and inactivated within a few milliseconds and remain closed and non-conducting throughout the plateau phase 
of the cardiac action potential. In certain pathologic conditions including mutations in the sodium channel gene 
SCN5A associated with the long QT-3 syndrome or disease states such as hypoxia, heart failure, and post-
myocardial infarction remodeling, sodium channels remain open or open again during the action potential 
plateau.9-16 The late channel openings allow a sustained current off sodium ions to enter myocardial cells 
throughout systole.7This current has been referred to as late, sustained or persistent to distinguish it from the 
peak or transient INa. The amplitude of late INa is less than 1% of peak INa but it is sufficient to prolong action 
potential duration (APD).40 Thus, although the amplitude of late INa is small, because it persists for hundreds of 
milliseconds the influx of sodium by this mechanism may be substantial.41 Transmural heterogeneity in the 
magnitude of late INa can cause transmural heterogeneity of APD that may have pathophysiological significance 
as a mechanism of ventricular tachyarrhythmias.41  
Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells and the late sodium 
current plays a pivotal role in this process.9-13,43 Sodium overload leads to calcium overload of myocardial cells 
with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased 

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impairment of diastolic relaxation of myocardium further augmenting risk of ischemia and myocardial damage 
(Figure 8).  
Breaking this pathway by late sodium channel blockers might bring numerous benefits to jeopardized 
myocardium. The entire class I of antiarrhythmic drugs consists of sodium channel blockers and none of them 
was proven to be effective in preventing arrhythmic events. But none of them had unique abilities to block 
selectively late sodium channel without significantly affecting peak current. Ranolazine, a FDA-approved anti-
angina drug, was recognized over the last few years as a unique late sodium channel blocker which might have 
antiarrhythmic properties and properties toward reducing mechanical dysfunction of the left ventricle with long-
term benefits in high-risk patients with cardiomyopathies. There is no clinical trial evaluating ranolazine (the 
only late sodium channel blocker on the market) in high-risk ventricular arrhythmia patients and we believe that 
such a trial is very much needed to advance treatment modalities for management of patients at risk for 
ventricular arrhythmias and to elucidate further mechanisms leading to adverse outcome in heart failure patients.      
 
 
 
 
 
 
Figure 8. Increases in intracellular sodium concentration 
([Na+]i) in ischemic cardiac myocytes cause calcium (Ca2+) 
overload via the Na+-Ca2+ exchanger (NCX) leading to 
contractile dysfunction and cellular injury. A pathologically 
enhanced late Na+ current (late INa) contributes to the [Na+]i-
dependent Ca2+ overload. Ranolazine, by decreasing the 
magnitude of the pathologically enhanced late INa, prevents or 
reduces Ca2+ overload and attenuates the accompanying 
deleterious consequences,43 
B.4. Significance of the Trial  
We believe that the trial with late sodium channel blockade ranolazine in high-risk ICD patients is very much 
needed since there is no safe and effective treatment for a large number of patients with high risk of ventricular 
tachyarrhythmias. It is of interest to clinicians, NHLBI, and patients to improve the very low survival of patients 
at increased risk of ventricular tachyarrhythmias. The sooner we learn about the potential antiarrhythmic 
benefits of late sodium current blockade in a clinical trial, more patients will have their lives saved and 
prolonged (assuming that our hypothesis will be confirmed).  
 
High-risk patients with ICDs in place constitute a unique group of patients in whom antiarrhythmic properties of 
this new drug could be very well documented by interrogating implanted devices with stored information on 
arrhythmic events occurring during a long-term follow-up. Simultaneously, ICDs provide a safety measure just 
in case of unlikely (based on preclinical and clinical experience) possibility of drug-induced proarrhythmia in 
studied patients.   
 
It is worth stressing that late sodium current blockade represents a new scientifically attractive concept of 
antiarrhythmic therapy after two decades of no significant developments in pharmacologic treatment of 
ventricular arrhythmias.  Conducting such a trial might open the door to the development of an entire line of 
compounds targeting the late sodium current as their main mode of antiarrhythmic action.  
 

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The use of ranolazine in the proposed study does not need an IND since ranolazine is currently marketed and the 
route, dose level, and patient population do not significantly alter risk and the study will be conducted in 
keeping with IRB and consent requirements. The regulations are designed to not encumber reasonable studies of 
approved drugs. FDA provided the letter confirming that IND is not needed.  
 
C. PRELIMINARY STUDIES 
C.1. Prior Studies Documenting High Risk of Cardiac Events in ICD Patients 
There is vast evidence for high risk of cardiac events in high-risk patients who are qualified for ICD therapy for 
secondary or primary prevention of mortality. The sections below document event rates in populations of 
interest for this project and illustrate that there is a tremendous need of developing therapies to reduce the 
excessive risk of arrhythmic events and mortality, which cannot be addressed by ICD therapy alone.       
C.1.1. Secondary Prevention of Mortality 
The Antiarrhythmics vs. Implantable Defibrillator (AVID) trial was the first study that documented significant 
reduction of mortality with ICD therapy in patients with cardiac arrest, documented ventricular tachycardia or 
ventricular fibrillation.22 Individual patient data from the AVID trial, and two similar studies: the Cardiac Arrest 
Study Hamburg (CASH) trial, and the Canadian Implantable Defibrillator Study (CIDS) trial were merged to 
perform a meta-analysis of a total of 1,866 patients evaluated regarding measures aiming to reduce secondary 
prevention of mortality.44 As shown in Figure 9, ICD therapy was associated with a significant reduction in 
mortality, however, long term mortality in the ICD arm remained high indicating that these patients require 
additional modes of therapies in addition to ICDs.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 9. Cumulative probability of death in 1,866 patients enrolled in clinical trials AVID, CIDS and CASH by treatment arm: 
amiodarone or ICD therapy.44  
 
Much newer data regarding the clinical course of patients qualified for secondary prevention of mortality with 
ICDs were presented by the OPTIC Study.7 The OPTIC Study was designed to determine whether amiodarone 
plus beta-blocker or sotalol are better than beta-blocker alone for prevention of ICD shocks in patients with 
predominantly secondary prevention indications for ICDs. Patients were randomized to receive treatment with 
amiodarone plus beta-blocker, sotalol alone, or beta-blocker alone for one year. The OPTIC study population 
consisted of 421 patients who had implanted ICDs within the past 21 days for inducible or spontaneous VT/VF 
(AVID, MADIT, MUSTT type of patients). Over 70% had spontaneous VT/VF (secondary prevention following 
AVID indications), and the remaining 30% of patients had induced VT/VF (primary prevention following 
MADIT/MUSTT indications).  Figure 6 (presented in section B.2) graphically shows that patients treated with 
beta-blockers have about 30% 1-year probability of developing VT/VF requiring ICD therapy. 
 

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Data from the control group of the Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular 
Tachycardia (SMASH-VT) trial demonstrated 33% 2-year mortality in secondary prevention patients who 
received their ICD for documented ventricular tachyarrhythmias or in primary prevention patients who 
experienced at least one arrhythmic event after implantation of device.33 
 
Therefore, there is substantial evidence documenting a very high risk of mortality and arrhythmic events in 
patients qualified to ICD therapy for secondary prevention of mortality. 
C.1.2. Primary Prevention of Mortality in Ischemic Cardiomyopathy 
In the section B.1, we referenced our MADIT II data,1 documenting the high risk of recurrent events in patients 
who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. Additional analyses 
performed purposefully for this application in these 169 patients demonstrated that a 2-year probability of a 
combined endpoint of VT/VF requiring ICD therapy or death was reached by 57% of patients who survived at 
least one appropriate ICD therapy (Table 1). 
 
Table 1. Probability of Cardiac Events in 169 MADIT II Patients with ICDs after First VT/VF Requiring ICD Therapy 
Event Type 
1 year rate 
2 year rate 
ICD Therapy for VT/VF  
27% 
49% 
ICD Therapy for VT/VF or Death 
33% 
57% 
ICD Therapy for VT/VF, CHF Hosp or Death  
41% 
66% 
 
It is worth emphasizing that among MADIT II patients there is a substantial proportion of patients who should 
be considered as high-risk at baseline (without need for documented arrhythmic events). Figure 10 shows the 
data from the MADIT II cohort fulfilling the entry criteria proposed for this application. The 2-year cumulative 
probability of ICD shock for VT/VF or death was 37%.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10. Cumulative 2-year probability of ICD shock for VT/VF or death in MADIT II patients with BUN>25mg/dl. 
 
When considering the composite endpoint of CHF hospitalization or death, Figure 11 shows cumulative 
probability of CHF hospitalizations or death reaching 40% at 2 years. The analysis of cardiac hospitalizations or 
death in these patients revealed 55% 2-year risk of this cardiac event.   
 
Our secondary endpoints also include analyses of repeated ICD therapies and repeated hospitalizations for 
cardiac causes. Figure 12 shows the intensity plot used for the analyses based on the Anderson-Gill method, 
reflecting repeated hospitalizations for cardiac causes in MADIT II patients with ICDs. There were 55 
hospitalizations for 100 patients in year 1 and 100 hospitalizations per 100 patients in year 2 (averaging 1 
hospitalization per patient over 2-year period). Regarding repeated ICD shocks, there were 23 shocks per 100 

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person-years, when counting one shock per day. When separate arrhythmia episodes (5-minute apart) were 
counted, this rate increases to 34 per 100 person-years.  The above preliminary data indicate high morbidity of 
patients with ICDs, which might be reduce by pharmacological treatment targeting ventricular arrhythmias and 
also influencing diastolic function of the left ventricle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 11. Cumulative 2-year probability of CHF hospitalization or death in MADIT II patients with BUN>25mg/dl. 
 
As mentioned earlier, the SCD-HeFT trial (which enrolled about one-half ischemic and one-half nonischemic 
cardiomyopathy patients in NYHA class II or III with EF≤35%),3 also documented high rates of mortality in 
patients with ventricular tachycardia or ventricular fibrillation requiring ICD therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 12. Cumulative intensity of repeated hospitalization for cardiac causes in MADIT II patients with ICDs. There were 55 
hospitalizations at 1 year and 100 hospitalizations at 2 years per 100 patients (intensity 0.55 and 1.0 respectively).  
C.1.3. Nonischemic Cardiomyopathy Patients  
The DEFINITE trial documented a beneficial role of ICD therapy in patients with nonischemic cardiomyopathy 
and low ejection fraction.24 In the DEFINITE trial, 16% of patients in the NYHA class II and 33% of patients in 
the NYHA class III reached the combined endpoint of ventricular tachycardia or ventricular fibrillation 
requiring ICD shock or death during a mean 30-month follow-up (Dr. Alan Kadish – unpublished data - 
personal communication on September 18, 2008).  
 

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In the MUSIC Study,45 which enrolled congestive heart failure patients in class II and III NYHA, we analyzed 
data for 263 patients with nonischemic etiology of cardiomyopathy with EF≤35%. There were 63 (24%) deaths 
over a median 44-month follow-up.  In 58 NYHA class III patients there were 21 (35%) deaths whereas in 205 
NYHA class II patients there were 42 (20%) deaths (hazard ratio for NYHA class III vs. class II = 1.99 (95% 
CI: 1.18-3.36; p =0.010).  
 
The estimated 2-year mortality rates were 22% in NYHA class III and 10% in NYHA class II (Figure 13). There 
were no data on arrhythmic events in this patient population, but mortality rates in NYHA class III patients 
indicate a high likelihood of a 30% 2-year event rates when considering combined arrhythmic endpoint 
considered for the proposed trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 13. Cumulative probability of survival in 263 patients with nonischemic cardiomyopathy by NYHA class enrolled in the 
MUSIC study 
 
Similarly, when using the 75th percentile of the BNP levels as a cut-off in the MUSIC patients, there was a 2-
fold increase in mortality in patients with BNP in the upper quartile of the distribution than in lower three 
quartiles (unpublished data).  
 
Both the DEFINITE and MUSIC studies document that nonischemic cardiomyopathy patients in NYHA class 
III are at high risk of mortality. In addition, DEFINITE documented a high (21%) risk of appropriate ICD 
therapy in NYHA class III patients. These data indicate that nonischemic cardiomyopathy patients with NYHA 
class III should be considered as a very high-risk subgroup of these patients.   
 
C.2. Ranolazine as Antiarrhythmic Compound (In Vitro Data)  
Blockade of sodium channels by antiarrhythmic drugs is the principal mechanisms of action by class I 
antiarrhythmic drugs with all of them affecting the peak sodium current in addition to late sodium current. 
Ranolazine, a piperazine derivative with a molecular structure similar to lidocaine, was patented in 1986 and 
was developed as an anti-angina drug.  Ranolazine is a novel sodium channel blocker which inhibits late sodium 
current without significant effect on peak sodium current (no QRS changes). In isolated ventricular myocytes of 
dogs with chronic heart failure, ranolazine was found to inhibit peak INa and late INa with potencies 
(50%inhibitory concentrations) of 244 and 6.5 µmol/l, respectively.18  Ranolazine is about 38-fold more potent 
in inhibiting late INa than peak INa
18. For comparison, amiodarone is about 13-fold more potent in inhibiting late 
than peak INa.17 
 
Ranolazine decreases APD, measured at either 50% or 90% of repolarization (APD50 or APD90, respectively), 
and abolishes early after depolarizations (EADs) of guinea pig ventricular myocytes treated with ATX-II (Figure 
14).15   Ranolazine has been shown to have antiarrhythmic effects in a guinea pig in vitro model of the long QT-

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3 syndrome.46 Ranolazine similarly antagonized the proarrhythmic actions of combinations of ATX-II and either 
the IKr blocker E-4031 or the slow delayed-rectifier current (IKs) blocker chromanol 293B.6 In the same long QT-
3 model, ranolazine was found to suppress spontaneous and pause-triggered ventricular arrhythmic activity 
caused by a diverse group of IKr blockers (that is, moxifloxacin, cisapride, quinidine and ziprasidone).46 
 
Beat-to-beat variability of APD are often observed in myocytes from failing dog hearts, in ischemic preparations 
and in myocytes exposed to either ATX-II or to drugs that prolong the QT interval. An increased dispersion of 
repolarization is associated with electrical and mechanical alternans and is proarrhythmic.2 There are data 
indicating that late INa contributes to beat-to-beat variability of APD.8 Ranolazine reduces the variability of APD 
in single ventricular myocytes from dogs with heart failure10and in myocytes exposed to ATX-II.15 Thus, 
inhibition of late INa with ranolazine and other sodium channel blockers suppresses EADs and decreases 
dispersion and variability of repolarization.15,16,46,47. 
 
Figure 14.Ranolazine attenuates the effects of the Anemonia 
sulcata toxin (ATX-II) on APD and EADs in guinea pig 
ventricular myocytes.  
 
 
(A) Recordings of action potentials from a ventricular 
myocyte in the absence of drug (control, (a)), in the presence 
of 10 nM ATX-II (b), and in the presence of ATX-II and 
increasing concentrations (1, 3, 10 and 30 {micro}M) 
ranolazine (c-f). An EAD is indicated by the arrow in 
recording (b).  
 
 
(B) Concentration-response relationship for ranolazine to 
decrease APD in the presence of 10 nM ATX-II. All values 
of APD in the presence of ranolazine are significantly 
different from ATX-II alone (p < 0.01).15 
 
 
 
Impaired left ventricular relaxation and increased left ventricular end-diastolic pressure are early manifestations 
of myocardial ischemia, caused in part by calcium overload. In ischemic myocardium, ranolazine has the 
potential to disrupt the consequences of cell hypoxia by reducing excess late Na+ influx, thereby reducing 
calcium overload and ultimately reducing the concomitant increase in left ventricular wall tension. Reduction in 
diastolic left ventricular wall tension would decrease myocardial oxygen requirements and reduce vascular 
compression, allowing more coronary blood flow to the affected area. Since this calcium overload is coupled to 
an increase in sodium due to an enhanced late INa, inhibition of this increased late INa by ranolazine attenuates 
the LV mechanical dysfunction associated with ischemia and cardiomyopathies. Ischemia increases LV diastolic 
pressure, a phenomenon attributed to calcium overload triggered by a rise in [Na+]i. In rabbit and rat isolated 
perfused hearts, ranolazine has been shown to significantly reduce ischemia-related increases in LV diastolic 
pressure and creatine kinase release (Figure 15). 9 
 
 
 
 
 
 
 
Figure 15.  Effect of ranolazine on the left 
ventricular 
end 
diastolic 
pressure 
(LVEDP) and creatine kinase release of 
rabbit 
isolated 
Langendorff-perfused 
hearts. Values significantly different (p < 
0.05) from drug vehicle.49The anti-
ischemic 
and 
antiarrhythmic 
properties of ranolazine are believed 

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to be related to its ability to block late sodium current, decrease intracellular calcium overload, and improve 
diastolic relaxation of the ventricles. Ranolazine also inhibits IKr, ICa, and IKs. The IKr blocking effect contributes 
to minor action potential duration prolongation and QT prolongation. However, it does not cause early after 
depolarizations and ventricular tachyarrhythmias (similar to the antiarrhythmic profile of amiodarone).  
 
Importantly, increased activity of late sodium current with subsequent calcium overload and antiarrhythmic and 
functional effects of ranolazine have been documented in myocardium from failing human hearts from patients 
who underwent cardiac transplantation for dilative nonischemic cardiomyopathy.13 Therefore, both ischemic and 
nonischemic cardiomyopathy patients might benefit from late sodium channel blockade, since sodium and 
calcium overload is present in both these conditions. 
 
  
Figure 16. Post repolarization refractoriness (PRR) – left panel, and overall dispersion of repolarization – right panel in (A) amiodarone, 
(B) dronedarone, and (C) sotalol groups. f P o .05  as compared with baseline  (A) amiodarone, (B) dronedarone, and (C) sotalol groups. 
P<0.05 as compared with baseline (Frommeyer et al. 50). 
 
In December 2012, Frommeyer et al.50 reported data on concomitant use of ranolazine with amiodarone, 
dronedarone, and sotalol in rabbit hearts. Ranolazine increased post-repolarization refractoriness as compared 
with amiodarone or dronedarone alone. In contrast to amiodarone and dronedarone, acute application of sotalol 
increased dispersion of repolarization. Additional treatment with ranolazine did not further increase spatial or 
temporal dispersion (Figure 16). Additional treatment with ranolazine reduced the number of VT episodes in 
sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone.  

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C.3 Data Regarding Clinical use of Ranolazine 
Large clinical trials conducted with ranolazine to date were focused on evaluating predominantly anti-ischemic 
and anti-angina properties of the drug. The Monotherapy Assessment of Ranolazine in Stable Angina 
(MARISA)52 and subsequent Combination Assessment of Ranolazine in Stable Angina (CARISA)51 trials 
enrolled patients with chronic effort angina and documented exercise-induced ischemia. The primary efficacy 
end point for both studies was symptom-limited exercise duration at trough plasma concentrations at 12 hours 
after dosing. MARISA was a monotherapy study that tested a 3-fold dose range of ranolazine.52 All 3 doses 
resulted in a significant increase in exercise duration compared with placebo (P 0.005) in a dose-dependent 
fashion. The CARISA study tested 823 patients with chronic angina once-daily atenolol (50 mg), once-daily 
diltiazem (180 mg), or once-daily amlodipine (5 mg).51 The results showed that, compared with placebo, 
ranolazine significantly increased symptom-limited exercise duration. The ERICA study53 evaluated the average 
number of angina attacks per week. During the 6-week treatment, the mean number of angina episodes per week 
decreased to 3.2 in the placebo group and 2.8 in the ranolazine group (P=0.028). Mean nitroglycerin use per 
week decreased to 2.6in the placebo group and 2.0 in the ranolazine group (P=0.014) without a significant 
change in heart rate or blood pressure. 
 
The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary 
Syndrome(MERLIN TIMI 36)54 study was a large double-blind placebo controlled trial of patients with an acute 
coronary syndrome receiving contemporary therapy, who have had chest pain within the 48 hours before 
randomization, ST depression or abnormal biomarkers, diabetes mellitus, or a TIMI risk score ≥3. The primary 
end point of the trial was the composite of cardiovascular death, myocardial infarction, or recurrent ischemia. 
Intravenous administration of the drug was followed by oral ranolazine or placebo. The MERLIN trial did not 
show significant difference in the primary endpoint with hazard ratio = 0.92 (95% CI: 0.83-1.02; p=0.11). There 
was no difference in mortality between groups and there was a significant reduction in the episodes of recurrent 
ischemia (HR = 0.87; 95% CI: 0.76-0.99; p=0.030). The MERLIN trial confirmed safety of a long-term 
administration of ranolazine, addressing initial concerns related to QT prolonging effects of the drug.    
 
In a subanalysis of the MERLIN trial, ranolazine contributed to a significant decrease in risk of VT episodes 
lasting 8 beats or longer in overall study population (Figure 17).55  
 
 
 
 
 
 
 
 
 
 
Figure 17. Kaplan-Meier estimated rates of the first occurrence 
of an episode of ventricular tachycardia lasting at least 8 
beats.55 
 
 
Relevant to this proposal that aims to evaluate the effects of ranolazine in predominantly heart failure patients, 
the MERLIN trial showed that in 585 patients with EF<40%, the 7-day Holter revealed a significant decrease in 
episodes of VT of least 8-beat duration in those treated with ranolazine (8.8%) vs. placebo (16.6%); hazard ratio 
= 0.53 (95% CI 0.34-0.84); p=0.005. A similar hazard ratio was reported for 1,069 patients with a prior history 
of heart failure.55  Additional analyses of MERLIN data showed that in patients who had BNP>80 pg/ml, 
ranolazine contributed to a significant reduction of the primary endpoint.  
The effects of ranolazine were evaluated in 4,543 patients from the MERLIN-TIMI 36 trial who had measured 
plasma levels of BNP at baseline.56 Patients were stratified using BNP>80 pg/ml. The primary endpoint was a 
composite of cardiovascular death, myocardial infarction, or recurrent ischemia. There were 1,935 patients with 
elevated BNP and in these ranolazine reduced the primary endpoint (HR 0.79; 95%CI 0.66 – 0.94, p=0.009) 

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contrasting with the lack of detectable effect in those with a negative BNP result (Figure 18; p-interaction = 
0.05). It is believed that in our proposed study the majority of randomized patients will have elevated BNP 
levels. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure18. Cumulative probability of cardiac event defined as cardiovascular death, recurrent ischemia or myocardial 
infarction in patients with and without elevated BNP on ranolazine or placebo. 
 
Concomitant use of ranolazine with amiodarone, have been reported by Fragakis et al.57 in 51 consecutive 
patients with AF eligible for pharmacologic cardioversion. Patients were randomized to intravenous amiodarone 
for 24 hours or to intravenous amiodarone plus oral ranolazine 1,500 mg at time of randomization. Conversion 
within 24 hours was achieved in 22 patients (88%) in amiodarone plus ranolazine group versus 17 patients 
(65%) in amiodarone alone group. There was no evidence for QTc prolongation associated with adding 
ranolazine to amiodarone.   
 
Bunch et al.58in a small study documented that ranolazine proved effective in reducing VT burden and ICD 
shocks in patients with VT refractory to antiarrhythmic treatment. Ranolazine was given on top of amiodarone 
therapy in 11 subjects and on top of sotalol in one subject. Addition of ranolazine was effective in controlling 
acute arrhythmia.  
 
 
 
 
 
 
 
 
 
 
Figure 19. The time-based outcomes of patients 
treated with ranolazine. Three time periods are 
shown: the index hospitalization, the steady state 
(day 3) to hospital discharge, and 3 months to last 
follow-up. All patients presented with ICD 
therapies and both sustained and nonsustained 
VT. Sustained VT, nonsustained VT, and ICD 
therapies were all reduced during the study 
observation 
period 
(Bunch 
et 
al.58). 
 
At the same time, there were no 
significant changes in QRS duration 
128±31 ms vs. 133±31 ms and no significant changes in QTc: 486±32 ms vs. 495±31 ms. In those patients with 
ischemic substrate, recurrent VT was observed after hospital dismissal during antiarrhythmia drug dose 

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reduction or if the ranolazine was discontinued due to side effects.  Long term effects (Figure 19) were very 
encouraging.  
 
C.4. Safety of Ranolazine  
 
Ranolazine blocks IKr current and might cause mild QT prolongation. In the dose range of 500 to 1000 mg twice 
daily, ranolazine increases the QTc (Fridericia) by an average of 2 to 5 ms.59 The incidence of "QTc outliers" in 
lead II with the use of the Fridericia correction for a QTc of > 500 ms was 0.7% at the 1000 mg twice daily 
dose, and a QTc increase of > 60 ms was observed in 2.3% patients. Ranolazine is contraindicated in patients 
with 
preexisting 
QT 
prolongation, 
on 
QT-prolonging 
drugs, 
or 
with 
hepatic 
impairment.   
 
Despite QT prolongation there is no evidence for ranolazine causing torsade de pointes ventricular tachycardia. 
Data from several clinical trials (MARISA, CARISA, ERICA, MERLIN) 51-53, 54-56 with over 4,000 patients on 
ranolazine treated for a long time showed that there was no evidence for torsadogenic effects of ranolazine. 
Especially, the MERLIN trial54 well documented that there was no increase in mortality in patients taking 
ranolazine, and there was a significant decrease in the risk and rate of complex ventricular arrhythmias.  
 
These clinical observations are in agreement with pre-clinical data from Dr. Antzelevitch’s group showing that 
ranolazine acts similarly to amiodarone which also prolongs the action potential duration and QT interval, but 
reduces 
transmural 
heterogeneity 
of 
repolarization 
and 
eliminates 
earlyafterdepolarizations.16  
 
We evaluated the safety of ranolazine in patients long QT syndrome type 3 caused by mutations of the SCN5QA 
gene and as shown in Figure 20, incremental plasma concentration of ranolazine was associated with 
progressive dose dependent QT shortening (by 26±3ms on average) further clinically confirming a late sodium 
blockade mechanism of this novel drug.20  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 20. Dose-dependent QTc shortening in LQT3 patients in response to ranolazine.20 
 
Additional unpublished data from the MERLIN trial database support that concomitant use of ranolazine with 
antiarrhythmic medication seems safe (Dr. Luiz Belardinelli and Dr. Ewa Prokopczuk from Gilead Sciences – 
personal communication from September 12, 2013).  There were 25 patients who took amiodarone and 
ranolazine for prolonged period of time of several months. In parallel, 48 took amiodarone and placebo for a 
prolonged period of time. There were 4 deaths (all sudden deaths) in 48 amiodarone plus placebo treated 
patients and none in 25 amiodarone plus ranolazine treated patients. Regarding sotalol, 6 patients were taking 
sotalol with ranolazine for a prolonged time of several months. In parallel, 8 patients were on sotalol and 
placebo for a prolonged time. There were 2 death (both sudden) among sotalol and placebo patients and none in 
6 sotalol and ranolazine patients. These are still anecdotal data, but there is no indication of harm due to this 
combination. 
 
 

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C.5. Prior Experience of Investigators 
This application is prepared by a group of investigators experienced in conducting clinical trials and studies 
(more information is provided in clustered application describing Data Coordination Center). Major studies 
conducted and coordinated by our group include: 
 
- 
International Long QT Syndrome Registry – an ongoing multicenter collaborative project aiming to advance 
knowledge about this genetic disorder characterized by abnormal repolarization in the ECG and a propensity 
to ventricular tachyarrhythmias and sudden cardiac death.  Over 1,200 proband-identified families are 
enrolled in the registry with over 15,000 family members.  
- 
Multicenter Automatic Defibrillator Trials II (MADIT II) – multicenter trial of 1,232 post infarction patients 
with EF≤30% which demonstrated the benefit of implantable cardioverter-defibrillators in primary 
prevention of cardiac death (31% reduction in mortality).  
- 
Multicenter Automatic Defibrillator Trial – Cardiac Resynchronization Therapy (MADIT – CRT) – This 
trial with 1,820 subjects already randomized and currently in a long-term follow-up aims to determine 
whether cardiac resynchronization therapy combined with ICD (CRT-D) is superior to ICD therapy alone in 
preventing progression of heart failure in patients with ICD indications but in NYHA class I or II (which is 
not currently approved indication for CRT).   
- 
Multidisciplinary Study of Right Ventricular Dysplasia -This NIH study, aims to establish improved 
diagnostic criteria for identifying patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. 
Over 140 probands were enrolled in the study with significant complexity of core lab operations.  
- 
Risk Stratification in MADIT II Type Patients – NIH-funded study aiming to determine risk factor for 
predicting cardiac events in patients qualified for ICD therapy for primary prevention of sudden death.  
 
There are over 80 original papers published over the last 5 years by our group in relationship to the above and 
other related studies.    
 
D. RESEARCH DESIGN AND METHODS 
D.1. Introduction 
Prevention of sudden death by an ICD therapy is applied to a large number of patients (>100,000 per year only 
in the US) who are at increased risk of mortality and arrhythmic events including patients after cardiac arrest 
(secondary prevention of mortality), post infarction patients with low ejection fraction, and nonischemic patients 
with depressed left ventricular function (primary prevention of mortality). In a population of patients with 
implanted ICDs, there is a substantial proportion of patients who are at high risk of developing arrhythmic 
events and who remain at high risk of death despite implanted devices.1-3,6-7 It is well documented that patients 
who develop ventricular tachycardia/fibrillation requiring ICD therapy present with high likelihood of repeated 
arrhythmia episodes requiring ICD therapies.1-7 As documented by the MADIT II and SCD-HeFT sub studies, 
the risk of death in patients with documented ICD therapy is a 2-3-fold higher than in patients with no 
arrhythmic events.1,3 
 
High-risk individuals with ICDs might benefit from pharmacological therapies aiming to decrease the risk of 
arrhythmic events and to decrease the likelihood of hospitalizations for cardiac causes and death. Late sodium 
current blockade is a novel pharmacological approach that could be used in patients at high risk for ventricular 
arrhythmias and high risk for cardiovascular morbidity and mortality. This trial will test the hypothesis that 
administration of ranolazine, a unique late-sodium current blocker, will reduce the rate of a composite primary 
endpoint consisting of arrhythmia endpoint consisting of ventricular tachycardia or ventricular fibrillation 
(VT/VF) requiring antitachycardia pacing (ATP), ICD shocks or death. 
 
D.2. Specific Aims of the Proposed Trial 
D.2.1. Primary aim of the study 
To determine whether ranolazine administration will decrease the likelihood of a composite arrhythmia endpoint 
consisting of ventricular tachycardia or ventricular fibrillation (VT/VF) requiring ATP therapy, ICD shocks, or 
death. 

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In addition to the above primary specific aim, there are several secondary aims that will be addressed in this trial 
by utilizing data from detailed records of arrhythmia episodes provided by implanted devices, and 
comprehensive data on hospitalizations during follow-up.  
D.2.2. Secondary aims of the study 
1. to determine whether ranolazine administration will decrease the likelihood of a composite arrhythmia 
endpoint consisting of VT or VF requiring ICD shock or death (while excluding VT/VF requiring just ATP)   
2. to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints 
consisting of hospitalization for cardiac causes (including not only hospitalization for heart failure, but also 
hospitalizations related to cardiac arrhythmias, myocardial infarction or ischemia) or death, whichever occurs 
first.  
3. to determine whether ranolazine administration will decrease the likelihood of a composite secondary 
endpoint consisting of CHF hospitalization or death; 
4. to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac 
causes. 
5. to determine whether ranolazine administration will decrease the likelihood of repeated ICD therapies (not 
just first therapy) 
6. to determine whether ranolazine administration will decrease the likelihood of inappropriate shocks (a 
decrease in episodes of atrial fibrillation triggering inappropriate therapy) evaluating the risk of first and risk 
of repeated inappropriate shocks. 
7. to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured 
by the 6-minute walk test (6MWT) and in the quality of life measured by the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
8. to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of 
ventricular tachyarrhythmias (including torsade de pointes).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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D.3. Overall Design of the Trial 
This trial is proposed as a double-blind placebo-controlled trial (Figure 21).  
 
 
 
Figure 21. Design of trial. 

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Study Drug Assignment: At randomization, patients will be assigned to the ranolazine or placebo study 
medication treatment group. Study drug must be initiated within one calendar day following randomization. The 
dose of 1000 mg twice daily of ranolazine will be used in the active drug arm. However, as recommended for 
clinical use, each patient will be started on a 500 mg twice daily dose at baseline, for 1 week, with subsequent 
increase to 1000 mg twice daily after 1 week.   
 
QT Prolongation: For patients on anti-arrhythmic therapy at the time of randomization, their ECG will be 
checked after 1 week on 500 mg twice daily dose. If there is evidence of QTc prolongation > 60ms after 1 week 
of therapy with 500 mg twice daily, the subject will remain in the study off study drug. The ECG will be 
checked again at week 2 on 1000 mg twice daily dose and the dose will be adjusted to 500mg twice daily, if 
there is a significant (> 60ms) prolongation of QTc in comparison to pre-dose ECG (pre-implant ECG for newly 
implanted ICD patients or post-implant ECG in newly implanted CRT-D patients; baseline study ECG in 
patients with older devices. In a large MERLIN trial,51 with 3,279 patients randomized to ranolazine only 31 
(0.9%) patients required dose adjustment due to prolongation of QT. 
 
Creatinine Clearance (CrCl):  
 
a. Prior to Randomization, CrCl will be performed prior to randomization to assess renal function.  If CrCl is 
< 30ml/min, the patient will be excluded from the study. If CrCl is ≥ 30 ml/min, study drug will be initiated 
per protocol. 
 
b. Week 2: CrCl will be repeated at week 2 for those patients who have a CrCl of < 60 ml/min, prior to 
randomization. If at the week 2 visit, their CrCl is < 30 ml/min, study drug will be discontinued but patient 
will remain in the study for follow-up. If CrCl is ≥ 30ml/min, study drug will be continued at their current 
dose, per protocol.  
 
c. Week 4: CrCl will be repeated at week 4 for those patients who have a CrCl of < 60 ml/min: if ≥ 30 ml/min 
they can remain on their current dose of study drug, as per protocol. If CrCl < 30 ml/min, study drug will be 
discontinued, but patient will remain in the study for follow-up. 
 
d. Months 6, 12 and 24: CrCl will be repeated at months 6, 12 and 24 for all patients taking study drug in the 
trial. If CrCl < 30 ml/min the study drug will be discontinued, but patient will remain in the study for follow-
up. If CrCl ≥ 30 ml/min patients will remain on their current dose of study drug, as per protocol. If a patient 
develops severe renal impairment (< 30ml/min) anytime during the study, the patient will be taken off study 
drug, but patient will remain in the study for follow-up. 
 
Liver function tests (LFTs): LFTs (AST and ALT only) will be performed at baseline, months 6, 12 and 24 
with concomitant acquisition of ECGs to determine whether patients with elevated LFTs have evidence for QTc 
prolongation.  Patients should be on optimal medical therapy including high usage of beta-blockers, ACE-
inhibitors, and statins, in addition to antiarrhythmic therapy as recommended at the time consent is obtained. 
Patients and their primary physicians will be informed regarding potential for interactions of ranolazine with 
other drugs/substances that might be affected by ranolazine administration including 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.  
 
Concomitant Medications: 
 
CYP3A Inhibitors: Although, strong and moderately strong CYP3A inhibitors will exclude a patient from 
enrolling in the study we will allow randomized subjects who require strong CYP3A inhibitors (including  
ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir and saquinavir), or 
moderate CYP3A inhibitors (including diltiazem, verapamil, aprepitant, erythromycin, fluconazole and  
grapefruit juice or grapefruit-containing products), during their participation, to remain in the study: 
Randomized subjects, who require a strong CYP3A inhibitor, will be taken off study drug while on these class 
of drugs. Randomized subjects who require a moderate CYP3A inhibitor during the course of the trial will be 
administered ranolazine in the dose of 500 mg twice daily, while taking these classes of drugs.  

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CYP3A Inducers: Patients who require inducers of CYP3A such as rifampin, rifabutin, rifapentin, 
phenobarbital, phenytoin, carbamezepine and St.John’s wort should be excluded from the study at the time of 
consent, or if already randomized, should be taken off study drug while on these class of drugs. 
 
Digoxin: Concomitant use of Ranolazine and digoxin results in increased exposure to digoxin. Therefore, in 
patients taking digoxin, the dose of digoxin will be decreased in half (See section E.4.2 for further details).  
 
Statins: The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each doubled in 
healthy subjects receiving 80mg once daily and Ranexa 1000 mg twice daily. Therefore the dose of simvastatin 
in patients on any dose of Ranexa will be limited to 20mg once daily, when ranolazine is co-administered. 
Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with Ranexa 
(1000 mg twice daily) in healthy volunteers.  Therefore the dose of study drug in patients on 80 mg daily of 
atorvastatin will be limited to 500 mg twice daily, at the time of randomization. These patients will therefore 
not require a week 2 ECG to check QTc prolongation if they are also on an antiarrhythmic medication. Patients 
who may require 80 mg of atorvastatin during the study will also be limited to 500 mg twice daily while taking 
this medication. Patients on < 80mg atorvastatin do not require a dose reduction in study drug. 
 
Metformin: In subjects with type 2 diabetes mellitus, concomitant use of Ranexa (1000 mg twice daily) and 
metformin results in increased plasma levels of metformin. Patients on > 1700 mg/day will have their dose of 
study drug limited to 500 mg twice daily during the study. Patients on > 1700 mg/day of metformin, at the time 
of randomization, will have their dose of study drug limited to 500 mg twice daily during the study. These 
patients will therefore not require a week 2 ECG to check QTc prolongation, if they are also on an 
antiarrhythmic medication. Patients who may require > 1700 mg/day of metformin during the study will also be 
limited to 500 mg twice daily while taking this medication. Patients on <1700mg/day metformin do not require 
a dose reduction in study drug . 
 
Liver Cirrhosis: Patients who develop liver problems and/or scarring (cirrhosis) of your liver should be taken 
off study drug for the remainder of the study. 
D.3.1. Device Programming 
The programming of implantable devices was revised to accommodate uniform approach to identification of 
arrhythmic endpoints. The following pre-specified ICD tachyarrhythmia programming parameters must be 
followed:  
A. Tachyarrhythmia Programming 
 
Primary Prevention ICD Indication Patients, without Prior VT/VF treated with ATP or shock, or prior ICD 
documented NSVT consisting of at least 10 beats at heart rate of at least 170 bpm: 
 
- Monitoring zone 170-190 bpm [no therapy including no ATP] 
- VT zone 190-220 bpm; initial duration of 5 seconds for Boston Scientific devices or equivalent in number of 
beats for other devices (See table below for details); ATP x1; 2nd therapy: shock (DFT +10J or max) 
- VF zone >220 bpm with ATP turned off and shock after initial duration of 2.5 seconds for Boston Scientific 
devices or equivalent in number of beats for other devices  
- RV pacing set at 40 bpm when programmed in VVI mode 
 
Secondary Prevention ICD Indication Patients, or Primary Prevention Patients with Prior VT/VF treated with 
ATP or shock, or with untreated ICD-documented NSVT:  
 
- Monitoring zone 170-190 bpm [no therapy including no ATP] 
- VT zone 190-220 bpm; detection initial duration of 2.5 seconds for Boston Scientific devices or equivalent in 
number of beats for other devices**(see table below for details); ATP x1; 2nd therapy: shock (DFT +10J or 
max) 

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**If evidence for documented VT or NSVT < 190 bpm: VT zone ≤20 bpm below clinical VT and ATP x1; 
2nd therapy: shock after 5 seconds 
- VF zone >220 bpm with ATP turned off and shock after initial duration of 2.5 seconds for Boston Scientific 
devices or equivalent in number of beats for other devices 
- RV pacing set at 40 bpm when programmed in VVI mode 
 
B. Antibradycardia Programming  
 
Antibradycardia programming should follow best practice and seek to minimize ventricular pacing in patients 
without CRT devices. 
- In patients without sinus or AV node disease, antibradycardia pacing should be programmed to VVI 40. 
- In patients with complete heart block, rate-responsive pacing should be programmed as appropriate: VVIR 
for those with permanent AF and DDDR for those with sinus rhythm. 
- In patients with sinus node dysfunction and prolonged AV conduction: DDI or DDD (or DDIR or DDDR) 
with lower rate of between 40-60 bpm with a long AV delay to limit right ventricular pacing; AAI<-->DDD 
(Medtronic) or SafeR (Sorin) or AV Search+ (or Reverse Mode Switch in Boston Scientific) or Ventricular 
Intrinsic Preference (VIP® Extension) (St. Jude). 
- In those with CRT, the device should be programmed to optimize % BiV pacing. A lower rate limit of 40-60 
bpm and optimization of AV delays (consistent with local standard practice) should be considered. 
 
Programming of delay in VT/VF zones by manufacturer 
Manufacturer 
Primary Prevention 
No Prior VT/VF 
Secondary Prevention or  
Primary Prevention with Prior VT/VF 
or ICD documented NSVT  
VT zone1 
 (190-220 bpm) 
VF zone1 
 (>220 bpm) 
VT zone1** 
(190-220 bpm) 
VF zone1 
 (>220 bpm) 
Total Duration* 
7 sec 
4.5 sec 
5 sec 
4.5 sec 
 Boston Scientific 
Initial Duration 
 = 5 sec 
Initial Duration 
 = 2.5 sec 
Initial Duration 
 = 2.5 sec 
Initial Duration  
= 2.5 sec 
 Medtronic 
VT initial beats to 
detect = 24 
VF initial beats to 
detect = 18/24 
VT initial beats to 
detect = 16 
VF initial beats to 
detect = 18/24 
 St. Jude Medical 
24 
18 
16 
18 
 Biotronik 
24 
18/24 
16 
18/24 
 Sorin/ELA 
8/12 
(Y=12;X%=75%) 
VT Persistence = 16 
8/12 
 (Y=12;X%=75%) 
VF Persistence = 10 
8/12  
(Y=12; X%=75%) 
VT Persistence = 8 
8/12  
(Y=12; X%=75%) 
VF Persistence = 10 
* Includes detection time and initial duration or respective number of beats 
**If evidence for documented VT or NSVT < 190 bpm: VT zone ≤20 bpm below clinical VT 
1 cut off heart rates for respective devices: 
- BSci 170 / 190 / 220 
- MDT 171 /  188 / 222 
- SJM 171 / 190 / 222 
- Biotronik 171 / 188 / 222 
- Sorin/ELA 170 / 190 / 220 
These stringent programming criteria will ensure that only severe arrhythmias are treated.   
 
 

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D.3.2. In –Person and Telephone Follow-up visits 
Patients will be followed for 24 months on average (ranging from 6 months to 36 months) with in person 
follow-up visits scheduled 1 and 2 weeks (for patients on anti-arrhythmic therapy only, at the time of 
randomization) after randomization and subsequently every 6 months. Additional visits will be conducted every 
3 months either via telephone or in person. It is expected that on average randomized patients will have two 
additional unscheduled visits related to unexpected adverse drug experiences (i.e. adverse drug experiences not 
consistent with the drug package insert). Table 2 shows the schedule of data collection and testing. 
 
Table 2: Data Collection and Study Testing Acquisition Schedule  
Reportable  
Data Items 
In 
Person 
Visit 
Telephone or In Person 
Visit 
In Person Visit 
Telephone 
or In 
Person 
Visit 
In 
Person 
Visit 
Baseline 
 
1 
Week 
Visit 
2 
Week 
Visit 
4  
week 
visit 
6 
month 
Visit 
12 
Month 
Visit 
24 
Month 
Visit 
18/30/
36 
Month 
Visits 
Remaining 
visits every 3 
months 
(3, 9, 15, 21, 
27, 33) 
Unsched
uled 
Visits* 
7+3 
days 
14+3 
days 
28+3 
days 
+14 
days 
+14 
days 
+14 
days 
+14 
days 
+14 days 
Creatinine 
Clearance 
(Blood Sample) 
**** 
 
**** 
**** 
 
 
 
 
 
 
Clinical/Device 
Data 
 
 
 
 
 
 
 
 
 
 
Review of 
Concomitant 
Medications 
** 
 
 
 
 
 
 
 
 
 
Study drug 
dispensing 
   
 
 
 
 
 
 
 
 
 
Physical 
Assessment 
 ** 
 
 
 
 
 
 
 
 
 
6 Minute Walk 
Test 
** 
 
 
 
 
 
 
 
 
 
Kansas City 
Cardiomyopathy 
Questionnaire 
** 
 
 
 
 
 
 
 
 
 
ECG *** 
** 
 
 
 
 
 
 
 
 
 
Liver Function 
Tests 
(Blood Sample) 
** 
 
 
 
 
 
 
 
 
 
Pregnancy test † 
** 
 
 
 
 
 
 
 
 
 
BNP & Future 
Storage  
(Blood sample ) 
** 
 
 
 
 
 
 
 
 
 
Device 
Interrogation 
§ 
 
 
 
 
 
 
 
 
 
Adverse Events 
‡ 
 
 
 
 
 
 
 
 
 
 
* It is expected that additional unscheduled visits will occur in relation to unexpected adverse drug experiences 
   (i.e. adverse drug experiences not consistent with the drug package insert). 
** Obtain prior to start of study medication (can be obtained prior to randomization). 
*** Required pre-implant ECG can we copied from patient’s chart and required post-implant pre-drug ECG can be 
obtained from patient chart or recorded during baseline visit. 
**** Obtain prior to randomization. Only required at week 2 if CrCl < 60 ml/min at baseline. If CrCl < 30ml/min at week 
2, patient will discontinue study drug. Only required at week 4 if  CrCl <60 ml/min at week 2. At week 4, if <30 ml/min the 
study drug needs to be stopped. .If ≥30 ml/min they remain on current dose of study drug per protocol.  
†Women at age <55 years old will be required to undergo pregnancy test to rule out pregnancy.  

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‡ Information regarding adverse events will be collected throughout the study apart from pre-specified visits. 
§ Initial Device Check to reconfirm programming of implanted device.  
 The 1-week and 2-week in-person visits/ECGs are mandatory, for patients on concomitant antiarrhythmic therapy at the 
time of randomization. Patients not on concomitant antiarrhythmic therapy at the time of randomization will have phone 
visits at week 1 and week 2 for adverse events and concomitant medication review.   
 
D.4. Study Population: Inclusion and Exclusion Criteria 
The study population will consist of 1,440 high-risk patients with ischemic or 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: 
 
A. 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). 
 
B. Primary Prevention Patients 
 
The following two groups of primary prevention patients are eligible: 
 
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. 
  
Untreated NSVT documented by ICD interrogation should be identified based on electrogram, not just based 
on non-verified count/log of the device. Local physician’s diagnosis of NSVT of at least 10 beats in a row 
with a heart rate of at least 170 bpm is required to avoid qualifying patients with atrial arrhythmias identified 
by the device as NSVT. 
 
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: 
 
a. BUN ≥ 26 mg/dl  
b. QRS ≥ 120ms  
c. Documented evidence of Atrial Fibrillation, 
d. NSVT documented by ECG/Holter   
e. >500 Ventricular Premature Beats (VPBs) documented  in a 24-hour Holter.  
 
Patients receiving ICDs (or CRT-Ds) for primary prevention of mortality constitute a high-risk subset of the 
overall patient population with MADIT II and SCD-HeFT indications for ICDs, as described in section C of this 
application.  
 
a. BUN: BUN level is frequently obtained at the time of device implantation as part of routine pre-procedure 
evaluation. Most recent BUN within 2 calendar years prior to date consent obtained should be used. If 
BUN level is not available, it should be performed as part of the screening for the study. 
 
b. QRS:  Current (pre-implant or most recent) ECG obtained within 2 calendar years prior to implant with a 
non-paced rhythm, should be used to determine QRS duration based on automatic ECG readout.  
 

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c. Atrial fibrillation: documented evidence for existing atrial fibrillation or atrial flutter rhythm on ECG or 
documented ECG evidence for paroxysmal atrial fibrillation during past 2 calendar years prior to date 
consent obtained. For patients with preexisting pacemaker with ventricular pacing, paced QRS duration 
will not be used as a criterion qualifying patients with primary prevention (only non-paced beats could be 
used to employ QRS duration criterion). Patients with atrial fibrillation or history of atrial fibrillation on 
antiarrhythmic therapy are eligible to be enrolled. 
d. NSVT: Documentation of NSVT on ECG/Holter/telemetry within 2 years prior to implant of device or 
after implant of device.  
 
e. VPBs: Frequent >500 VPBs per 24 hour, Holter recording should be performed within 2 years prior to 
implant of device or after implant of device. 
D.4.1.Inclusion Criteria 
Patients who meet all of the following criteria at the time of consent could be included in this clinical 
investigation: 
 Secondary or primary prevention patients with ischemic or nonischemic cardiomyopathy  who meet current 
guidelines for ICD or CRT-D device therapy and meet the above definition of high-risk patients 
 Patient on stable optimal pharmacologic therapy for the cardiac condition, including use of anti-arrhythmic 
therapies such as (but not limited to) amiodarone, sotalol, dronedarone, and dofetilide. 
 Patient greater than or equal to 21 years of age without upper limit 
 
D.4.2. Exclusion Criteria 
Since the study will enroll and subsequently randomize patients who are routinely implanted with ICD devices, 
exclusion criteria will be limited mostly to conditions precluding or limiting implantation of devices based on 
currently approved indications.. 
 
Specifically, patients who meet any one of the following criteria at the time of consent will be excluded from 
this clinical investigation: 
 Patients 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 
 Patients receiving first device with enzyme-positive myocardial infarction with the past 3 calendar months 
prior to date consent obtained 
 Patients 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 
 Patients 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, rifapentin, phenobarbital, phenytoin, carbamezepine 
and St.John’s wort 
 Patients with inherited arrhythmia disorders such as Brugada’s, ARVD, LQTS or hypertrophic 
cardiomyopathy 
 Patients who are pregnant or plan to become pregnant during the course of the trial (patients at child bearing 
age who use prescribed pharmaceutical contraceptives could be enrolled) 
 Patients with irreversible brain damage from preexisting cerebral disease 
 Patients 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. 

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 Patients with chronic renal disease with creatinine >2.5 mg/dl or creatinine clearance <30 ml/min. 
 Patients participating in any other clinical trial 
 Patients unwilling or unable to cooperate with the protocol 
 Patients who live at such a distance from the clinic that travel for follow-up visits would be unusually 
difficult 
 Patients who do 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.  
 Patients unwilling to sign the consent for participation 
D.4.3. Inclusion of women 
Inclusion of women and minorities in the trial is discussed in more detail in Section E.9. Women at age <55 
years old will be undergoing pregnancy test to rule out pregnancy (unless they underwent hysterectomy).  
 
D.5. Follow-up and Endpoints 
In addition to 1- and 2-week initial visits, (mandatory in-person clinic visit for those patients on anti-arrhythmic 
therapy at the time of randomization) patients will have long-term follow-up clinic visits scheduled every 6 
months and follow-up visits either in person or via telephone every 3 months.  The follow-up clinic visit will 
include dispensing study medication, acquisition of clinical information regarding cardiac events and changes in 
medication or device programming and data on arrhythmias from interrogated ICDs. Floppy disks or other 
electronic storage media with interrogation data will be forwarded to the Rochester Clinical Core Laboratory for 
central reading and interpretation. The ICD Interrogation Committee will adjudicate all arrhythmic events. The 
Endpoint Adjudication Committee will review and categorize all cardiac hospitalizations and death cases and 
will have access to data from the ICD Interrogation Committee.     
 
Primary endpoint of the study will be defined as a composite endpoint consisting of VT/VF requiring ATP 
therapy, ICD shock, or death, whichever occurs first  
 
Secondary endpoints will include:  
- ICD shock for VT or VF or death, whichever occurs first 
- hospitalization for cardiac causes or death, whichever occurs first;  
- CHF hospitalization or death, whichever occurs first;  
- number of repeated hospitalizations for cardiac causes over time;  
- number and frequency of repeated arrhythmic events (VT/VF) over time;  
- inappropriate therapy;  
- functional capacity measured by the 6-minute walk test;  
- quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ).   
 
Hospitalizations for cardiac causes will include all hospitalizations related to the following frequent conditions: 
heart failure, ventricular tachyarrhythmias, unstable angina, myocardial infarction, atrial fibrillation/flutter or 
atrial tachyarrhythmias, high blood pressure, ICD related hospitalizations, pulmonary embolism, and other 
cardiac conditions not listed here.   
 
Information regarding all cardiac events including all hospitalizations, arrhythmia episodes, and death cases will 
be provided by enrolling centers to central database and designated endpoint adjudication committees will 
categorize these events. There will be an endpoint committee adjudicating hospitalizations and death and a 
separate committee adjudicating arrhythmia episodes documented by ICDs. The committees will be blinded 
regarding randomization of evaluated patients. We considered using remote device monitoring, but since the 
study medications need to be dispensed to the patients every 3 months we rely on this personal visits to acquire 
data from interrogated ICDs. The events that occur after final visit but prior to withdrawal or death will be 
obtained.  
 

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When already enrolled, patients with VT/VF events observed during follow-up will be allowed to be treated 
with antiarrhythmic medications (as per physician discretion) to be added on top of the study drug (ranolazine or 
placebo). Similarly, patients requiring antiarrhythmic medications for supraventricular arrhythmias including 
atrial fibrillation will be allowed to be treated with antiarrhythmic medications.  
 
D.6. Planned enrollment and randomization 
The trial will randomize 1,440 patients in approximately 100 enrolling centers over a period of approximately 
27 months following enrollment (date consent obtained). This rate of randomization is equal to about 0.67 
patients per month per center on average and is comparable to our recently completed MADIT-CRT trial of 
1820 randomized patients where the average randomization rate per center per month was around 0.65 patients 
per month. We chose to use conservative estimates regarding the rate of randomization. However, we believe 
that our study could randomize 2-3 patients per month per center on average since volume of ICD implants is 
high in select enrolling centers.   
 
D.7 Timeline of the Study 
The first 6 months of the study will be devoted to start-up activity needed to establish the organization of the 
study, the database, and to obtain RSRB approvals in all the enrolling centers. The enrollment activity with 
subsequent randomization is planned for subsequent 27 months with up to 20 additional months of follow-up 
allowed for (uncertain due to the stopping rule) and 1 month for final adjudication of events. The last 6 months 
will be devoted to closeout activities and final data analyses (Table 3): 
 
 
          Table 3. Timeline of Planned Activity for the Trial 
 
 
D.8. Quality of Life 
Quality of life data will be acquired at baseline and after 12 and 24 months of therapy using the Kansas City 
Cardiomyopathy Questionnaire (KCCQ).60,61 It is hypothesized that quality of life measures will improve after 
treatment with ranolazine in comparison to placebo.   
 
D.9. The 6-minute Walk Test (6MWT) 
The 6MWT is routinely used in evaluating functional status in heart failure studies,62,63 and will provide 
additional insight regarding the effect of tested drugs on functional/physical capacity of randomized patients. 
The 6MWT will be performed at baseline and repeated at 12-month- and 24-month follow-up visits. It is 
hypothesized that there will be improvements in the distance achieved during the 6MWT for patients assigned to 
ranolazine relative to those on placebo. 
 
D.10. Blood Samples for BNP and Future Research  
Blood samples in the amount of 10 ml (2 teaspoons) will be collected in all randomized patients at baseline and 
at the 12-month follow-up visit to determine changes in levels of Brain Natriuretic Peptide (BNP) over time and, 
if the patient consents, an additional 10 ml (2 teaspoons) will be collected at baseline and the 12-month follow-
up visits for future research on heart failure. It is hypothesized that ranolazine with its expected beneficial 
effects on LV systolic and diastolic function will contribute to a significant decrease in levels of BNP, a marker 
of heart failure advancement, and marker of risk in heart failure patients. The core lab for analyzing BNP will be 
at the University of Rochester Medical Center Laboratories. Blood samples will be sent directly to URMC 
Laboratories, where they will be analyzed using the FDA cleared Elecsys Pro-BNP Immunoassay method. 
Methodology of blood drawing, shipping and storing will follow standard procedures in operations for years in 
clinical trials coordinated by the University of Rochester Medical Center.   
 

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The budget of the trial allows for the analysis of the BNP levels, which could provide an objective insight into 
the effect of treatment. However, the budget does not cover analyzing numerous other biochemical markers or 
genetic markers of interests. Using the same blood samples, when the data and blood collection is completed, we 
intend to apply for additional funding specifically focused on testing novel biochemical and genetic markers, 
and at that time we will outline full detailed plan of such analyses. The blood samples will be stored for future 
additional analyses pending future funding. These analyses might include additional biochemical, metabolic 
markers and genetic markers identifying patients with cardiac events and/or identifying patients with differential 
response 
to 
ranolazine 
therapy.  
 
Among several possible future biomarkers, we intend to study: 1) serum markers of increased collagen synthesis, 
primarily procollagen type III N-terminal amino peptide (PIIINP) is the best overall index for detecting 
increased collagen synthesis and myocardial fibrosis in heart failure; 2) inflammatory markers including 
interleukin-6, interleukin-1β; and transforming growth factor-β1; 3) genetic polymorphisms of genes reflecting 
variation in the CYP3A enzymatic system metabolizing ranolazine; 4) genetic polymorphisms of the SCN5A 
sodium channel gene and genes influencing function of sodium homeostasis in myocardial cell; 5) genetic 
polymorphisms of the ryodine receptor genes and other known and newly identified genes related to 
intracellular calcium handling. The final list of the biomarkers of interest will be established few years from now 
when the study is completed and when there will be a possibility of taking advantage of newly identified 
biomarkers. 
 
D.11. TRIAL DESIGN; POWER, DURATION AND STATISTICAL ANALYSIS 
 
D.11.1. Endpoint Event Rates 
Based on recent preliminary unpublished data from the MADIT Risk Stratification Study and from the MADIT-
CRT trial, we revised our estimate of the 2-year cumulative endpoint rate to be 25% in the placebo arm of the 
trial (instead of original 30%). We maintain the same level of reduction of primary events: for the ranolazine 
arm (R), we expect at least a 25% reduction in risk, after allowing for the possibility of 10% cumulative 
crossovers to placebo (within 2 years) ─ that is,  a hazard ratio (HR) of 0.75. This implies a 2-year cumulative 
event rate in R of 19% [=  1 - (1 - 0.25)0.75], representing a 24% reduction in 2-year cumulative event rates.  We 
expect no crossovers from P to R.  We allow for losses to follow-up at the rate of 5% per year. 
 
D.11.2.Significance Level and Power 
The null hypothesis is that the true cumulative probability curves for time to first endpoint event are identical in 
the R and P arms (implying a HR of 1.0).  The alternative hypothesis is that the curve for the R arm is below that 
for the P arm, implying a reduction in risk of a first endpoint event.  Power computation is focused on a constant 
hazard ratio (HR) of 0.75, a 25% reduction in ongoing risk, an amount deemed worthy as clinically relevant, 
although a HR of 0.667 is considered quite possible.  The trial is designed to have a significance level of 0.05 
(2-sided) and 80% power at a constant HR of 0.75.  See the table below for resulting power at other HRs; power 
is 98% at a HR of 0.667. 
D.11.3. Recruitment and Randomization 
We will randomize 1440 patients in approximately 100 centers.  The randomization is expected to require 33 
months at an average rate of 44 per month, or 0.54 patients per center per month.  Consented patients will be 
randomized equally to the R and P arms, with randomization stratified by enrolling center, by type of device 
(ICD vs. CRT-D), within center, and by prior history of VT/VF/cardiac arrest within device type.  No further 
stratification is really feasible.  We assume balance between treatments within each device type is more critical 
than within ischemic and non-ischemic patient groups, or other possible risk categories.  
D.11.4. Sequential stopping rule 
A trial that continues follow-up until a pre-specified number of endpoints have accumulated, and based on a log 
rank test, would require 380 endpoint events.  At the anticipated randomization rate, loss rate and endpoint event 
rates, a larger sample size and/or longer follow-up time would be required. 

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We have chosen instead a sequential stopping rule with triangular stopping boundaries, similar to that used in 
the MADIT and MADIT-II trials.21 The expected number of events needed to reach a termination boundary is 
greatly reduced, although some risk of a longer trial is encountered.  We chose a specific boundary as provided 
by PEST software64 (as well as our own) that would meet the significance level and power requirements. 
The trial is to be monitored by periodically fitting a proportional-hazards regression model with treatment arm 
and six presumed risk factors as covariates (see ANALYSIS section below) and stratified by enrolling center.  
The resulting score-test statistic, Z, for testing nullity of a treatment effect, when plotted against its variance V, 
behaves like a Brownian motion with β, the regression coefficient for treatment effect, as its drift 65  The statistic 
Z quantifies any difference between treatment arms R and P in estimated time-to-endpoint curves. Its variance V 
(roughly equal to the accumulated event count divided by 4) quantifies statistical information. This computation 
will be done monthly, once 20 events have been accumulated, and submitted to the DSMB chair and statistician.  
A plot of Z versus V, starting at the origin, will continue until it reaches one of the two boundaries: 
           14.8153 + 0.101103*V  (upper)     and     -14.8153 + 0.303309*V   (lower)  
and truncated at V = 130.  (The boundaries may be adjusted to recognize the discrete-time monthly 
monitoring.65)  Upon reaching a boundary, the trial is to be terminated in favor of R if Z reaches the upper 
boundary and therefore p ≤ 0.05.  If Z first reaches the lower boundary with p ≤ 0.05 (that is, prior to V = 
18.585), the trial will be terminated with a conclusion that P is superior to R ─ i.e., that ranolazine increases risk 
of endpointing.  If Z reaches the lower boundary with p > 0.05 (V> 24.24), or along the vertical strip at V =130, 
the null hypothesis of no difference between R and P cannot be rejected.  The p-value is appropriately adjusted 
for the stopping boundary.60Theplot should vary around a line from the origin with slope β = -log(HR), with HR 
the hazard ratio for treatment effect (R:P) 
Power at various true HRs is given in column 2 of the table below. In column 3 are given the numbers of events 
expected upon reaching termination.  Also listed are the associated expected trial durations. [See the Technical 
Note below.]  Computations of duration assume recruitment of 1440 patients in 33 months, a cumulative event 
rate in the placebo arm of 25% at 2 years, and losses to follow-up occurring at an annual rate of 5%

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D.11.5. Trial Power and Duration@ 
True 
HR 
Power 
(in 
%)* 
Events** at 
Termination 
Estimated Trial Duration 
(months) 
Upper 
Quartile## 
Total 
Duration## 
Recruit 
Add’l 
F-u 
Extra# 
Total 
1.00 
2.5 
191 
27 
0 
1 
28 
250 
35 
0.90 
17 
248 
33 
2 
1 
36 
320 
42 
0.85 
35 
270 
33 
4 
1 
38 
346 
45 
0.80 
58 
273 
33 
5 
1 
39 
350 
46 
0.75 
80 
253 
33 
4 
1 
38 
322 
44 
0.70 
93 
271 
33 
1 
1 
35 
271 
40 
0.65 
99 
177 
39 
0 
1 
30 
220 
36 
@ All durations are measured from July 1, 2012.  Due to the delayed start-up, and according to the revised 
Accrual Milestones, we act as if recruitment is carried out evenly over the 33 month period July 2012 through 
March 2015, with 130 patients every 3 months. 
* probability of a positive trial      
** in the two arms together. The actual number is random and highly variable, depending on how the trial 
develops; what is tabled is the expected number to reach a stopping boundary (that is, averaged over many such 
trials under the same conditions).  However, any particular trial can require as many as 130*4=520 events (V = 
130), although it is highly unlikely ─ with probability < 0.001. 
 #  The extra month is allowance for endpoint adjudication time.  Again, total duration is the expected duration 
under the stated conditions, but actual duration may vary. `Duration’ is measured from the time enrollment is 
underway at most centers until the trial ends. 
  ## The last two columns give the upper quartile of the number of events at termination and the corresponding 
trial duration. 
As seen in the table, under the stated assumptions, whatever the true hazard ratio, the trial is expected to require 
at most 38 months once the speed up of randomization begins, with the trial estimated to end in August 2015 
leaving time to allow for closeout and analysis; 44 months duration would still allow closeout and analysis 
within a one-year no-cost extension.   However, these computations are based on the very conservative 
assumption of a 25% 2-year event rate in the placebo arm whereas the revised eligibility will likely lead to a 
higher event rate since higher proportion of patients with prior VT/VF will be expected. Any increase in the 
event rate will speed up termination of the trial.  Also, a smaller HR will shorten duration of the trial. 
D.11.6. Analysis 
At the end of the trial, a p-value for the primary hypothesis, an estimate of the true hazard ratio for treatment 
effect, and 95% confidence limits for the true hazard ratio will be determined, by methods adjusted to the 
sequential stopping rule.65 The primary analysis will be a statistical test of treatment effect based on a Cox 
proportional-hazards regression analysis stratified by enrolling center ─ as used in the sequential monitoring ─ 
with six additional baseline covariates: ejection fraction, creatinine, age (all three numerical), ischemic status 
(binary), antiarrhythmic medication at enrollment (binary) and a 3-level variable identifying the following 
groups:  - ICD  and  no history of VT/VF/cardiac arrest at enrollment; - CRT-D and no history of 
VT/VF/Cardiac Arrest at enrollment; - history of VT/VF/cardiac arrest, whether prior to implantation of device 
or afterwards. Device type is not expected to have an effect on risk in this third subgroup. (This last subgroup 
does not distinguish between device types as they are not expected to have an effect on risk once VT/VF or a 
cardiac arrest has been experienced.  These risk factors were chosen as being those found to be relevant in 
corresponding (unpublished) analyses of data from the MADIT-II and MADIT-CRT trials. Computations will 
be done by software developed at the University of Rochester, and will be confirmed by use of PEST software.64  
Some additional events will likely be reported after formal trial termination (events that occurred prior to 
termination), and these will be incorporated in the final adjusted p-value, hazard ratio and confidence limits 
computations.66 

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D.11.7. Validation and Assumptions 
Computations of p-values are broadly valid, but estimation of HRs presume a (near) constant hazard ratio.  
Hence, interpretation of the HR estimates in the primary analysis depends on validating the proportional hazards 
assumption.  This will be done by computing HRs by both 3- and 6-month intervals, with tests for differences 
among the time-specific HRs. 
D.11.8. Sensitivity Analysis 
- Baseline covariate balance between arms: The primary analysis will be repeated including each (one at a 
time) baseline covariate in the regression model that is out of balance between arms. 
- Evaluation of various combinations of the 3 components of the composite endpoint: A competing-risk 
analysis for separate components of the endpoint, determining a hazard ratio R:P for each, will be carried 
out,67 in particular, for VT/VF requiring ATP, for ICD shock, for death, and for the first of ICD shock and 
death.  The last of these provides an evaluation of the original composite endpoint without inclusion of the 
VT/VF requiring ATP component.  Power for the others is not predicted, but power for the latter – namely 
ICD shock /death – is estimated to be 80% at a hazard ratio of 0.72. 
D.11.9. Treatment Interactions 
The primary analysis will be repeated (without adjustment for the stopping rule), adding each of a pre-specified 
list of covariates (if not already in the regression model), one at a time, and their interaction with treatment arm 
to the regression model, and tests for interaction carried out.  This will identify, to the extent feasible, different 
treatment effects of Ranolazine across subgroups identified by the covariate. 
- CRT versus ICD groups 
- Primary versus secondary prevention groups 
- Ischemic versus non-ischemic groups 
- Females versus males 
- Older versus younger 
- BNP> versus <= median 
- Diabetes mellitus (yes versus no) 
- Antiarrhythmic medication at baseline  
- Large centers versus small centers 
D.11.10.Technical Note 
The formula for the number N of events expected in a single arm of the trial, assuming recruitment of n patients 
to the arm in m months and then an additional f months of potential active follow-up, a monthly rate b of losses, 
and a monthly rate r of endpoint events, may be shown to be                                     
N   =   n*(r/s)*{1 – [exp (-s*f) – exp (-s*d)]/(m*s)}with s = r + b  and  d = m + f.                                  
(Derivation involves integration over exponentially distributed endpoints and losses and over uniformly 
distributed randomization.)  Computing N using the rate r for the P arm, and again with r replaced by HR*r for 
the R arm, and adding, gives the number of events expected in a trial of duration d months.  For the P arm, r = [-
log(1-0.22)]/24 = 0.0103526; and b = [-log(1-0.05)]/12 = 0.004274, n = 720 and m = 27.  Carrying out this 
computation for a list of f values, and various values of HR, provides corresponding pairs of values for total 
duration d and the corresponding total number of events.   This analysis ignores any potential effect of including 
six risk factors in the regression analysis, and is hence conservative. 
PEST software (or other sequential trial software) can provide the number of events expected at termination of a 
sequential trial, in column 3 of the table above.  Using the list of event-duration pairs, this leads to 
corresponding total duration (after adding in the additional month for adjudication time) for each row of the 
table.  The number 720 of patients in each arm was found by trial and error as that value n needed to assure 
satisfactory total duration times.  The last two columns of the table were similarly determined.   

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D.11.11. Secondary Analysis 
The primary analyses with primary endpoints are planned with 80% power to detect specified differences 
between the ranolazine and placebo arms. Secondary aims will likewise require power of 80% (or more), where 
possible. 
The first three secondary aims (see Section D.2) are similar to the primary aim except with different composite 
endpoints.  Hence, analysis of each will be similar to that for the primary aim, except that no adjustment for the 
sequential stopping rule will be feasible (as stopping is based on the primary composite endpoint).   
 
1. Secondary aim #1, as mentioned above, power for ICD shock /death is estimated to be 80% at a hazard ratio 
of 0.72. 
2. Secondary aim #2, in which hospitalizations for cardiac causes or death is the secondary endpoint, it is 
expected that at least 30% of patients in the placebo arm will reach this endpoint, leading to considerably 
more power than for the primary endpoint, namely 80% at a 25% reduction in the ongoing risk. 
3. Second aim #3 addresses the effect of ranolazine on the composite endpoint consisting of CHF 
hospitalization or death. We assume that a 2-year probability of this endpoint in the placebo arm should reach 
at least 20%, resulting in power exceeding 80% for detecting a 30% reduction in the ongoing risk of this 
endpoint.  
4. Secondary aim #4 is about repeated hospitalization for cardiac causes; for it, an Anderson-Gill regression 
analysis (comparable to Cox analysis for a first event), but with death as a competing risk,67,68 will be carried 
out to assess any difference in ongoing risk of repeated therapy in the two arms of the trial. Power at 
comparable risk reductions should exceed that for secondary aim #2; this is confirmed by analysis of 
comparable subsets in the MADIT II data.  
 
5. Secondary aim #5 is about repeated ICD therapies; for it, again (see aim #4 above) an Anderson-Gill 
regression will be carried out to assess any difference in ongoing risk of repeated therapy in the two arms of 
the trial. Power at comparable risk reductions should exceed that for the primary endpoint; this is supported 
by results from the azimilide SHIELD trial. 
6. Secondary aim #6 is about inappropriate shocks.  For first inappropriate shocks, a Cox regression analysis 
will be done while for repeated shock episodes, an Anderson-Gill analysis will be done; each of these will 
need to treat death as a competing risk.67,68   The rate of first inappropriate shocks at 2 years is expected to be 
16% (or more), allowing 80% power to detect a HR of 0.70.  Power to detect similar effects for repeated 
shock episodes will be greater. 
7. Secondary aim #7 is about safety of ranolazine therapy; each type of safety issue will be individually 
analyzed by use of ICD interrogation data, and summary statistics will be compiled.   
8. Secondary aim #8 is about quality of life (QoL ─ see Section D.8).  For each patient having both baseline and 
2-year QoL data, the change in QoL from baseline to 2 years will be determined and averaged over patients 
in each arm.  Comparison of mean changes in the two arms will be evaluated by a t-test.  We expect at least 
500 patients in each arm to have the needed 2-year QoL data (at least those recruited during the first 13 
months).  Earlier experience with the Kansas City Cardiomyopathy Questionnaire suggests a standard 
deviation for a single change in scores to be approximately 20.  This should allow 80% power to detect a 
difference between arms in mean scores of 2.5 points and 90% power to detect difference of 3.0 points. Mean 
scores are expected to be in the neighborhood of 30 to 40. 
 
  
 
For the 6MWT, we will compare distance achieved by patients at baseline and at 2-year follow-ups, again 
limited to those with both 6MWTs, as measure of physical functioning. The primary analyses will be focused on 
the 2-year time-point and similarly to the quality of life analyses, we expect that at least 500 patients will have 
these tests performed. Based on prior studies, a standard deviation for a single change in the distance of the 
6MWT is expected to be approximately 50 meters.  This should allow 80% power to detect a difference between 
arms in mean distance of 6.5 meters and 90% power to detect a 7.5-meter difference in mean distance of 350 
meters. 
 

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D.12 ORGANIZATION AND KEY PERSONNEL    
This proposal consists of two applications originating from the University of Rochester Medical Center, 
Rochester, NY: 1) Clinical Core (CC) managing the overall study, activity of enrolling centers and core labs, 
and 2) Data Coordination Center (DCC) responsible for data management and data analyses. The Clinical Core 
application will serve as the Leading Application with Dr. Wojciech Zareba as overall PI of the trial and CC 
with Suzanne Robertson, PhD as Program Manager. Dr. James P. Daubert will serve as Co-PI of Clinical Core. 
The Data Coordination Center (DCC) will be independent from the main study operation and will be directed by 
Dr. Arthur Moss with Mary Brown, MS, as Program Manager and Dr. Chris Beck, PhD, as :. Dr. David Huang 
will be chairing the ICD Interrogation Adjudication Committee and Dr. Jeffrey Alexis, MD will chair the Events 
Committee. 
 
Figure 18. Organizational Structure of the Trial. 
 
Similarly to other studies (including line of MADIT trials) conducted by the Heart Research Follow-up Program 
at University of Rochester Medical Center, the independence of the data coordination center and other 
operational components will be ensured by setting strict rules regarding access to the data. The steering 
committee consisting of several experts in the field will play a key role in overall oversight of the trial (Figure 
18).  
 
D.13.SHARING RESEARCH DATA 
The investigators of this research project and the University of Rochester will provide sharing of the research 
data in a manner that protects the privacy of study participants and is consistent with NIH guidelines on resource 
sharing with other investigators.  
 
Data will be shared with collaborators as soon as available, with local colleagues at seminars and talks, and with 
the scientific community at large by presentations at local, regional, national and international scientific 
meetings. Publications will be prepared in timely manner. Press interviews on important publications will be 
arranged through the University of Rochester, Office of Public Affairs. 
 
We welcome collaboration of scientist interested in utilizing data from this study. The de-identified data sharing 
with colleagues and organizations not participating in the study will be arranged based on the Data Sharing 

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Agreement ensuring: (1) a commitment to using the data only for research purposes; (2) a commitment to 
securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the 
data after analyses are completed; 4) a commitment to sharing results of these analyses with the Executive 
Committee of the study.  
 
We extensively exercise policy of sharing data for ongoing and past projects. As examples, the MADIT II data 
were shared with many researchers affiliated directly with the trial and with those not participating in the trial. 
As a result, there are over 30 original papers already published or in press exploring this reach database. A 
similar activity relates to data from the NIH-funded LQTS studies where data were widely shared and were used 
for publishing over 30 papers in last few years. Similar productivity and sharing was exercised in case of the 
NIH-funded THROMBO study, for which over 25 papers were published or in press. 
E. PROTECTION OF HUMAN PATIENTS 
E.1. Ranolazine 
Ranolazine is a piperazine derivative that was patented in 1986 and is an FDA approved an anti-angina drug. 
Ranolazine (Ranexa; CV Therapeutics Inc., Palo Alto, California) is manufactured in a sustained-release form 
that has a prolonged absorption phase with maximal plasma concentrations (Cmax) typically seen 4 to 6 hours 
after administration. The average terminal elimination half-life is about 7 hours after multiple dosing to steady 
state, and the peak/trough difference is 1.6-fold with dosing of 500 to 1000 mg twice daily. Steady state is 
generally achieved within 3 days of twice-daily dosing. Ranolazine plasma concentrations that are 
therapeutically effective for chronic angina are in the range of 2 to 6 μmol/L. 
 
Regarding the mechanism of action, ranolazine is a novel sodium channel blocker which inhibits late sodium 
current without significant effect on peak sodium current (no QRS changes). In isolated ventricular myocytes of 
dogs with chronic heart failure, ranolazine was found to inhibit peak INa and late INa with potencies 
(50%inhibitory concentrations) of 244 and 6.5 µmol/l, respectively.18  Ranolazine is about 38-fold more potent 
in inhibiting late INa than peak INa.18. For comparison, amiodarone is about 13-fold more potent in inhibiting late 
than peak INa.17 
 
E.2. Risk to the Patients 
E.2.1. Adverse Reactions: Clinical Trial Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. A total of 2,018 patients with chronic angina were treated with ranolazine 
in controlled clinical trials. Of the patients treated with ranolazine, 1,026 were enrolled in three double-blind, 
placebo controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks duration. In addition, 
upon study completion, 1,251 patients received treatment with ranolazine in open-label, long-term studies; 1,227 
patients were exposed to ranolazine for more than 1 year, 613 patients for more than 2 years, 531 patients for 
more than 3 years, and 326 patients for more than 4 years.  
 
At recommended doses, about 6% of patients discontinued treatment with ranolazine because of an adverse 
event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse 
events that led to discontinuation more frequently on ranolazine than placebo were dizziness (1.3% versus 
0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 
1000 mg twice daily are poorly tolerated.  
 
In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions 
(> 4% and more common on ranolazine than on placebo) were dizziness (6.2%), headache (5.5%), constipation 
(4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term, treatment studies, a similar 
adverse reaction profile was observed. 
 
 

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E.2.2. QT Prolongation 
Ranolazine blocks IKr current and might cause mild QT prolongation. In the dose range of 500 to 1000 mg twice 
daily, ranolazine increases the QTc (Fridericia) by an average of 2 to 5 ms.59 The incidence of "QTc outliers" in 
lead II with the use of the Fridericia correction for a QTc of >500 ms was 0.7% at the 1000 mg twice daily dose, 
and a QTc increase of >60 ms was observed in 2.3% patients. Ranolazine is contraindicated in patients with 
preexisting 
QT 
prolongation, 
on 
QT-prolonging 
drugs, 
or 
with 
hepatic 
impairment.   
 
Despite QT prolongation there is no evidence for ranolazine causing torsade de pointes ventricular tachycardia. 
Data from several clinical trials (MARISA, CARISA, ERICA, MERLIN)51-53,56 with over 4,000 patients on 
ranolazine treated for a long time showed that there was no evidence for torsadogenic effects of ranolazine. 
Especially, the MERLIN trial56 well documented that there was no increase in mortality in patients taking 
ranolazine, and there was a significant decrease in the risk and rate of complex ventricular arrhythmias.  
 
These clinical observations are in agreement with pre-clinical data from Dr. Antzelevitch’s group showing that 
ranolazine acts similarly to amiodarone which also prolongs the action potential duration and QT interval, but 
reduces 
transmural 
heterogeneity 
of 
repolarization 
and 
eliminates 
earlyafterdepolarizations.16  
We evaluated the safety of ranolazine in patients long QT syndrome type 3 caused by mutations of the SCN5QA 
gene and as shown in Figure 19, incremental plasma concentration of ranolazine was associated with 
progressive dose dependent QT shortening (by 26±3ms on average) further clinically confirming a late sodium 
blockade mechanism of this novel drug.20  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 19. Dose-dependent QTc shortening in LQT3 
patients in response to ranolazine.20 
 
E.2.3. Drug-drug Interactions 
The interactions with other drugs which need to be emphasized are as follows.  
Drugs such as diltiazem, a 
moderate CYP3A inhibitor increase ranolazine plasma levels, about 50 to 130 %; ranolazine has no significant 
effect on diltiazem pharmacokinetics. Ranolazine is a substrate and an inhibitor of P-glycoprotein. Verapamil, a 
drug that inhibits P-glycoprotein, increases the absorption of ranolazine with a 100% increase in ranolazine 
plasma levels. The drug label indicates that ranolazine is contraindicated in patients taking strong inhibitors of 
CYP3A, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and 
saquinavir; inducers of CYP3A, such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort;  and patients with liver cirrhosis.  Concomitant use of ranolazine and 
digoxin results in increased exposure to digoxin. The dose of digoxin should be adjusted.  Ranolazine increases 
digoxin concentrations 50% in healthy volunteers receiving Ranexa 1000 mg twice daily and digoxin 0.125 mg 
once daily. The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each doubled in 
healthy subjects receiving 80 mg once daily and Ranexa 1000 mg twice daily. The dose of simvastatin in 
patients on any dose of Ranexa should be limited to 20 mg once daily, when ranolazine is co-administered. Dose 
adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow 
therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranexa may increase plasma 
concentrations of these drugs. The exposure to CYP2D6 substrates, such as tricyclic antidepressants and 
antipsychotics, may be increased during co-administration with Ranexa, and lower doses of these drugs may be 

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required. In subjects with type 2 diabetes mellitus, concomitant use of Ranexa 1000 mg twice daily and 
metformin results in increased plasma levels of metformin. When Ranexa 1000 mg twice daily is co-
administered with metformin, metformin dose should not exceed 1700 mg/day. Metformin exposure was not 
significantly increased when given with Ranexa 500 mg twice daily. Therefore patients on >1700 mg/day will 
have their dose of study drug limited 500 mg twice daily at the time of randomization and at any time during the 
study. Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with 
Ranexa (1000 mg twice daily) in healthy volunteers.  Therefore the dose of study drug in patients on 80 mg 
daily of atorvastatin will be limited to 500 mg twice daily, at the time of randomization, and at any time during 
the study. 
 
E.3. Recruitment and Informed Consent 
Each patient will have the protocol described to them by one of the physicians or research coordinators at the 
enrolling centers.  Potential patients who meet inclusion/exclusion criteria will sit down with the coordinator or 
physician and have the opportunity to ask questions. . If the patient agrees to participate in the study, the patient 
will sign an “informed consent” form that is fully approved by the local IRB following local IRB consent 
administration regulations and then be randomized to a study medication treatment group provided all required 
pre-study drug initiation testing is performed.  Study drug must be initiated within one calendar day following 
randomization.  
 
E.4. Protection Against Risk 
The following measures will be implemented which are similar to currently approved recommendations 
regarding clinical use of ranolazine. 
E.4.1. ECG monitoring 
At randomization, patients will be assigned to ranolazine or placebo. The dose of 1000 mg twice daily of 
ranolazine will be used in active drug arm. However, as recommended for clinical use, each patient will be 
started on a 500 mg twice daily dose for one week with subsequent increase to 1000 mg twice daily at 2 weeks. 
For each   ECG will be checked at 1 week on 500 mg dose and next at 2 weeks on 1000 mg dose and the dose 
will be adjusted if there is a significant (>60ms)  prolongation of QTc in comparison to baseline ECG. In a large 
MERLIN trial,56 with 3,279 patients randomized to ranolazine only 31 (0.9%) patients required dose adjustment 
due to prolongation of QT. 
 
Since impairment of liver metabolism of ranolazine might increase its level and contribute to more pronounced 
QT prolongation, we will measure liver function tests in relationship to concomitantly acquired ECGs for QT 
measurements performed at baseline prior to study drug initiation and 3 times during follow-up (, months 6, 12 
and 24).  
E.4.2. Drug interaction 
Patients and their primary physicians will be informed regarding potential for interactions of ranolazine with 
other drugs/substances that might be affected by ranolazine administration per Ranexa package insert. 
 
To minimize the risk of digoxin toxicity, patients on digoxin will have decreased dose of this drug by 50% (i.e., 
0.250 mg to 0.125 mg). Based on the retrospective data from the DIG trial, digoxin might be beneficial if 
administered in lower doses. However, data from newer cohorts indicate that if heart failure patients are treated 
with beta-blockers and ACE-inhibitors, following current guidelines, digoxin administration is not associated 
with significant increase or decrease of the risk of mortality or combined endpoint of CHF hospitalization or 
mortality. In the recent study of 347 patients with long-term follow-up,71 hazard ratios for use of digoxin for the 
above endpoints were (HR=1.03; p=0.85 and 1.11;  p=0.52, respectively. These observations might indicate that 
even decreasing the dose of digoxin in patients randomized to placebo (in our proposed trial) should not have 
negative impact on their outcome.      
 
E.4.3. Implantable Cardioverter Defibrillators 

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All patients randomized in this study will have implantable cardioverter defibrillators (ICDs) in place. This 
treatment and monitoring modality will provide detailed data regarding arrhythmic events occurring during 
treatment. Simultaneously, ICDs provide a safety measure just in case of unlikely (based on preclinical and 
clinical experience) possibility of drug-induced proarrhythmia in randomized patients. In this regard, this patient 
population will be protected much more effectively than in usual drug studies conducted in non-ICD patients.  
E.4.4. Privacy  
Efforts will be made to maintain confidentiality of study data.  All study data will be coded with an 
unidentifiable study code.  The study coordinator for each enrolling center will maintain a key linking the 
patient’s name with study data.  The Rochester DCC will also maintain a master key in a password protected 
data form separate from the main database.  Medical records collected to determine study eligibility will be used 
only for this purpose and shredded when no longer needed.  This system has been used in the previous grant and 
has provided an adequate means for protecting patient identities. 
All information and data collected concerning patients or their participation in this investigation will be 
considered confidential by the DCC. No social security numbers will be collected by the DCC. All data will be 
handled in accordance with applicable local laws. Study Data collected during this investigation may be used by 
the DCC for the purposes of this investigation, publication, to support future research and/or other business 
purposes. All DCC data used in the analysis and reporting of this investigation will be without identifiable 
reference to specific patient name or other patient identifiers.   HIPAA authorization will be obtained from each 
patient by every enrolling center per local regulations.  
 
E.5. Data and Safety Monitoring Plan 
An Independent Data Safety and Monitoring Board (DSMB) will meet periodically, or as needed, to review the 
results of the trial and to evaluate any safety and efficacy issues that may arise during the course of the study. 
The ongoing trial data will be transmitted to the DSMB on a monthly basis. The Board will carry out periodic 
data review and will inform the study Principal Investigator on any safety concerns. The DSMB may 
recommend termination of the study at any time should prospective ethical or safety guidelines not be met. The 
DSMB will consist of individuals who are not involved in the trial. The above plan has been exercised from last 
30 years in numerous clinical trials conducted by our research group, the last of the trial which followed the 
same schema was recently completed the MADIT-CRT. Based on this experience, we are confident that we will 
be able to address proper management of data and execution of the DSMB responsibilities for the trial.  
 
A DSMB will consist of NIH-nominated individuals that are not involved with the study. The data will be 
transmitted to the board on a monthly basis; and a review of the data will be done every 4 months. The DSMB 
will meet in person once per year; remaining two meetings during each year will be organized as conference 
calls. The DSMB may terminate the study at any time they foresee increased risk to subjects, or any safety 
concern. 
 
E.6. Adverse Drug Experience Reporting 
The DSMB, Steering Committee and PIs will be responsible for ensuring prompt reporting of adverse drug 
experience findings to IRBs and the NIH that might indicate concerns regarding safety of tested therapy in 
randomized patients. This reporting will be performed following routines established at our organization for 
numerous past trials. Since this study is IND exempt following review by the FDA, post market reporting 
requirements as defined in 21 CFR 314.80 will be followed in this study.      
E.6.1. Definition of Adverse Drug Experience per 21 CFR 314.80 
Any adverse event associated with the use of a drug in humans, whether or not considered drug related, 
including the following: An adverse event occurring in the course of the use of a drug product in professional 
practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected 
pharmacological action. 
 

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Adverse experience reports will be collected at each clinic follow-up for all randomized patients in the 
electronic database. Patients will be provided with enrolling center contact information to report adverse 
experiences between follow-up visits to avoid delays if serious events occur.   
 
These can include but not limited to events meeting the definition of an adverse event that are: 
- Intercurrent illnesses  
- Significant worsening (change in nature, severity, or frequency) of the disease under study or other preexisting 
conditions  
- Adverse events occurring during diagnostic procedures  
- A laboratory or diagnostic test abnormality occurring after the start of the study (once confirmed by repeat 
testing) that results in the withdrawal of the participant from the study, requires medical treatment or further 
diagnostic work-up, or is considered by the study investigator to be serious and/or clinically significant.  
- Abnormalities in physical examination or vital signs that require clinical interventions or further investigations 
(after repeated confirmatory test) or are considered by the study investigator to be serious and/or clinically 
significant.  
- ECG, arrhythmias found on defibrillator interrogation and echocardiogram abnormalities that require clinical 
intervention (device reprogramming, invasive intervention, inpatient admission or pharmaceutical treatment). 
Preexisting conditions should be recorded at screening in the source documentation at the enrolling center 
(medical history) but should not be reported as adverse events unless the condition worsens (increases in 
frequency or severity to meet the serious adverse event definition described below) after randomization. 
Diagnostic and therapeutic invasive and non-invasive procedures (including surgeries) should not be reported as 
adverse events. However, the medical condition for which the procedure was performed should be recorded if it 
meets the criteria for an adverse event. 
E.6.2. Serious Adverse Drug Experience 
Adverse events are classified as either serious or non-serious. A serious adverse drug event (SAE) is any adverse 
event occurring at any dose, which results in any of the following outcomes or actions:  
 
- Death 
- Life-threatening adverse drug experience  
- Inpatient hospitalization or prolongation of existing hospitalization 
- Persistent or significant disability/incapacity (disruption of a person’s ability to conduct normal life functions)  
- Congenital anomaly/birth defect  
- Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition  
Patients should be unblinded only if (1) knowledge of the treatment assignment will change management or (2) 
the treating physician feels the information is critical for patient safety. Prior to disclosing a subject’s treatment 
assignment, the enrolling investigator will page the Clinical Monitoring Director to determine if disclosure is 
absolutely necessary. Disclosure of individual treatment assignment will be made by the enrolling investigator 
responsible for the care of the particular subject or by a physician designated specifically by the enrolling 
investigator only after disclosure has been determined to be the best course of action.   
E.6.3. Unexpected Adverse Drug Experience 
This is defined as an adverse drug experience that is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, 
but differ from the event because of greater severity or specificity. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic 
enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the labeling only listed cerebral vascular accidents. "Unexpected," as used in this 
definition, refers to an adverse drug experience that has not been previously observed (i.e., included in the 

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labeling) rather than from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
E.6.4. 15-Day Reporting 
The enrolling center shall report each adverse drug experience to the CCC that is serious as soon as possible but 
in no case later than 15 calendar days of initial receipt of the information by the center. 
 
E.7. Discontinuation Criteria/Early Termination 
If the DCC or NIH makes a decision to discontinue the study (e.g., slow randomization, unanticipated adverse 
event, or other scenario), the DCC will promptly inform all Investigators and IRBs as required along with 
detailed information on how randomized patients should be managed thereafter. All randomized patients in the 
trial will continue to be followed according to the protocol unless the DCC notifies the investigational centers 
otherwise.  No non-FDA approved treatment is being used in this study so the patient’s care should not be 
compromised if the study is terminated for any reason since all treatment is available to the patient external to 
the study.  
 
E.8. Data Tracking Including Enrollment, Randomization and Withdrawals 
Electronic data will be entered at the enrolling centers and transmitted to the DCC. This database permits data 
expansion, easy updating, and rapid retrieval; it has simplified report-generating routines; an audit trail 
component; and analysis data sets can be easily produced for transmission to the biostatisticians and the DSMB 
for analysis.  
 
All data will be subject to an extensive computer edit checking process for completeness, internal consistency, 
numerical values outside specified rational limits, invalid codes, subject identification errors, and date errors.  
Errors detected in the edit check process will be corrected before the data are transferred to the definitive data 
management system that is used for final data analysis or reports. The DCC will implement requirements for 
standardization of observations and objective application of definitions, and it will institute other measures of 
quality control as required.  It will provide monthly reports evaluating the study performance to the PI, enrolling 
centers and NIH as required.  In summary: 
 
- Enrollment, randomization, withdrawal and follow-up data (deaths, adverse events, etc.) will be submitted to 
the DCC. The DCC is responsible for the security and privacy of data with the electronic data entry system 
only accessible by unique username and password which can only be authorized by the DCC.  
- The DCC is responsible for verification of data completeness, progress of enrollment and randomization, 
statistical analysis, and summary reports. 
All case report forms (CRFs) must be entered into the electronic data entry system provided by the 
DCC.  Original source documents (e.g., worksheets, programmed parameters) must remain at the center in the 
patient binder. 
Any changes to the reported data should be reported to the DCC and should be entered into the electronic data 
management system provided by the DCC. 
 
E.9. Participation of Women and Minorities 
The data from the Heart Disease and Stroke Statistics 2008 Update69 published in Circulation in January 2008 
reported that in 2004, coronary disease death rates per 100,000 people were 194.2 for white males and 223.9 for 
black males; 114.7 for white females and 148.7 for black females, 119.2 for Hispanics or Latinos, 106.5 for 
American Indians or Alaska Natives, and 84.1 for Asians or Pacific Islanders. Between 70 percent and 89 
percent of sudden cardiac deaths occur in men, and the annual incidence is three to four times higher in men 
than in women. However, this disparity decreases with advancing age.  Data relevant for ICD-eligible 
population are provided in a study by Hernandez et al. published in 2007 JAMA.70 An observational analysis 
of13 034 patients admitted with heart failure and left ventricular ejection fraction of 30% or less and discharged 
alive from 217 hospitals was conducted. 

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Eligible patients consisted of 34% of women (11.8% black and 22.5% white), and 66% of men (17.6% black 
and 48.1% white). Among patients eligible for ICD therapy, 4615(35.4%) had ICD therapy at discharge (1614 
with new ICDs, 527with planned ICDs, and 2474 with prior ICDs). ICDs were used in 375 of 1329 eligible 
black women (28.2%), 754 of 2531 white women (29.8%), 660 of 1977 black men (33.4%), and 2356 of 
5403white men (43.6%) (P < 0.001). After adjustment for patient characteristics and hospital factors, the 
adjusted odds of ICD use were 0.73 (95% confidence interval, 0.60-0.88) for black men, 0.62 (95% confidence 
interval, 0.56-0.68) for white women, and 0.56 (95% confidence interval, 0.44-0.71) for black women, 
compared with white men. The differences were not attributable to the proportions of women and black patient 
sat participating hospitals or to differences in the reporting of left ventricular ejection fraction. 
 
Based on these data it is expected that women will constitute a one-third of eligible patients. A pro-active 
approach will be utilized in this trial to ensure that women are appropriately included in the study population. 
We will enrich proportion of women eligible for randomization to reach at least 33% of women in this study. 
Enrollment of women will be accomplished by establishing close collaboration between center PI 
(electrophysiologist) and its congestive heart failure physicians who usually follow large number of women 
eligible for ICD therapy. In order to force the proportion of females in the study population to be at least 25%, 
the following rule will be imposed at each enrollment center: The proportion of females randomized at the 
center will be monitored; at any time when this proportion is below 25% (and after four patients have been 
randomized), only females will be eligible for randomization at that center. Efforts to increase recruitment of 
minorities will also be made, but no formal rule like that for females can be imposed due to variations in 
minority populations.  However, center-specific targets for minorities will be established and monitored. 
Interpreter services made available to ensure adequate information, consent, and ongoing discussion. 
 
 

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REFERENCES 
1. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, Daubert JP, McNitt S, Andrews ML, Elkin AD; 
Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) Research Group. Long-term clinical course of 
patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110:3760-5. 
PMID: 15583079 
2. Goldenberg I, Moss AJ, Hall WJ, McNitt S, Zareba W, Andrews ML, Cannom DS; Multicenter Automatic Defibrillator 
Implantation Trial (MADIT) II Investigators. Causes and consequences of heart failure after prophylactic implantation 
of a defibrillator in the multicenter automatic defibrillator implantation trial II. Circulation 2006;113:2810-7. PMID: 
16769917 
3. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, Reddy RK, Marchlinski FE, Yee R, Guarnieri 
T, Talajic M, Wilber DJ, Fishbein DP, Packer DL, Mark DB, Lee KL, Bardy GH.  Prognostic importance of 
defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009-17. PMID: 18768944 
4. Seidl K, Hauer B, Schwick NG, Zahn R, Senges J. Comparison of metoprolol and sotalol in preventing ventricular 
tachyarrhythmias after the implantation of a cardioverter/defibrillator. Am J Cardiol 1998;82:744–748.PMID: 9761084  
5. Kettering K, Mewis C, Dornberger V, Vonthein R, Bosch RF, Kuhlkamp  V. Efficacy of metoprolol and sotalol in the 
prevention of recurrences of sustained ventricular tachyarrhythmias in patients with an implantable cardioverter 
defibrillator. Pacing Clin Electrophysiol 2002;25:1571–1576.PMID: 12494613 
6. Pacifico A, Hohnloser SH, Williams JH, Tao B, Saksena S, Henry PD, Prystowsky EN. Prevention of implantable-
defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter–Defibrillator Study Group. N Engl J 
Med 1999; 340:1855–1862. PMID: 10369848 
7. Connolly SJ, Dorian P, Roberts RS, Gent M, Bailin S, Fain ES, Thorpe K, Champagne J, Talajic M, Coutu B, Gronefeld 
GC, Hohnloser SH. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks 
from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006; 295:165–171. PMID: 
16403928 
8. Bokhari F, Newman D, Greene M, Korley V, Mangat I, Dorian P. Long-term comparison of the implantable 
cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable 
Defibrillator Study (CIDS). Circulation 2004;110:112-6. PMID: 15238454 
9. Valdivia CR, Chu WW, Pu J, et al.Increased late sodium current in myocytes from a canine heart failure model and 
from failing human heart. J Mol Cell Cardiol 2005;38:475–83.PMID: 15733907 
10. Undrovinas AI, Maltsev VA, Sabbah HN. Repolarization abnormalities in cardiomyocytes of dogs with chronic heart 
failure: role of sustained inward current. Cell Mol Life Sci 1999;55:494–505.PMID: 10228563 
11. Huang B , El-Sherif T, Gidh-Jain M, et al.Alterations of sodium channel kinetics and gene expression in the 
postinfarction remodeled myocardium. J Cardiovasc Electrophysiol 2001;12:218–25. PMID: 11232622  
12. Li GR, Lau CP, Ducharme A, et al. Transmural action potential and ionic current remodeling in ventricles of failing 
canine hearts. Am J Physiol Heart Circ Physiol 2002;283:H1031–41.PMID: 12181133 
13. Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schöndube FA, Tirilomis T, Tenderich G, Hasenfuss G, 
Belardinelli L, Maier LS. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts-
-role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol 2008;45:32-43. PMID: 18439620 
14. Sakmann B , Spindler AJ, Bryant SM, et al.Distribution of a persistent sodium current across the ventricular wall in 
guinea pigs. Circ Res 2000;87:910–4.PMID: 11073887 
15. Song Y , Shryock JC, Wu L, et al.Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in 
guinea pig ventricular myocytes. J Cardiovasc Pharmacol 2004;44:192–9.PMID: 15243300 
16. Antzelevitch C , Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent 
with antiarrhythmic properties. Circulation 2004;110:904–10.PMID: 15302796 
17. Maltsev VA, Sabbah HN, Undrovinas AI. Late sodium current is a novel target for amiodarone: studies in failing human 
myocardium. J Mol Cell Cardiol 2001;33:923–32.PMID: 11343415 
18. Belardinelli L , Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential drug target 
to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur 
Heart J 2004;6 (Suppl I) :13–7.PMID: 15449646 
19. Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function 
in patients with ischemic heart disease. Cardiovasc Drugs Ther. 1994; 5: 741–747.  PMID: 7873471 
20. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine Shortens Repolarization in Patients 
with Sustained Inward Sodium Current Due to Type-3 Long-QT Syndrome. J Cardiovasc Electrophysiol. 2008 Jul 25. 
PMID: 18662191 
21. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; 
Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in 
patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-83. PMID: 11907286 

Ranolazine in High Risk ICD Patients 
 
 
RAID Protocol Version 6.0 
 
 
 
 
 
 
Page 45 of 47 
September 5, 2014 
22. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal 
ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 
1997;337:1576-83. PMID: 9411221 
23. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, 
McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death 
in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for 
congestive heart failure. N Engl J Med. 2005;352:225-37. PMID: 15659722 
24. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, 
Sanders WE, Schaechter A, Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation 
(DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. 
N Engl J Med 2004;350:2151-8. PMID: 15152060 
25. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, 
Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, 
Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, 
Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, 
Tarkington LG, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac 
Pacemakers and Antiarrhythmia Devices); American Association for Thoracic Surgery; Society of Thoracic Surgeons. 
ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to 
Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia 
Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic 
Surgeons. J Am Coll Cardiol 2008;51:e1-62. PMID: 18498951 
26. Mittal S, Aktas M, Cygankiewicz I, McNitt S, Steinberg J, Solomon S, Wang P,    Moss AJ, Zareba W. Prognostic 
significance of holter-detected ventricular arrhythmias in MADIT-CRT patients. JACC 2011 (abstracts) 
27. Zareba W, Daubert J, Costantini O, et al. Risk stratification of ventricular tachycardia or ventricular fibrillation in 
postinfarction patients with EF≤35%: results from a multicenter ICD risk stratification study. Heart Rhythm, 2013; 10: 
S207 
28. Zareba W, Piotrowicz K, McNitt Scott, Moss AJ for MADIT II Investigators. Implantable Cardioverter-Defibrillator 
Efficacy in Patients With Heart Failure and Left Ventricular Dysfunction (from the MADIT II Population). Am J 
Cardiol. 2005;95:1487-91. PMID: 15950580 
29. Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, Amlie J, Carlsen J; Dronedarone Study Group. 
Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678-87. PMID: 
18565860 
30. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al. Combined cardiac resynchronization and 
implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 
2003;289:2685-94. PMID: 12771115 
31. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or 
without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-50. PMID: 
15152059 
32. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, et al. The effect of cardiac 
resynchronization on morbidity and mortality in heart failure. N Engl J Med; 2005;352:1539-1549. PMID: 15753115 
33. Reddy VY, Reynolds MR, Neuzil P, Richardson AW, Taborsky M, Jongnarangsin K, Kralovec S, Sediva L, Ruskin JN, 
Josephson ME. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657-
65. PMID: 18160685 
34. Ferreira-González I, Dos-Subirá L, Guyatt GH. Adjunctive antiarrhythmic drug therapy in patients with implantable 
cardioverter defibrillators: a systematic review. Eur Heart J 2007;28:469-77. PMID: 17227788 
35. Dorian P, Borggrefe M, Al-Khalidi HR, Hohnloser SH, Brum JM, Tatla DS,Brachmann J, Myerburg RJ, Cannom DS, 
van der Laan M, Holroyde MJ, Singer I, Pratt CM; SHock Inhibition Evaluation with azimiLiDe (SHIELD) 
Investigators.  Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias 
in patients with an implantable cardioverter defibrillator. Circulation 2004;110:3646-54. PMID: 15533855 
36. Kiyosue T , Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular 
myocytes. Circ Res 1989;64:389–97.PMID: 2536304 
37. Gintant GA, Datymer NB, Cohen IS. Slow inactivation of tetrodotoxin-sensitive current in canine cardiac Purkinje 
fibers. Biophys J 1984;45:509–12.PMID: 6324914 
38. Saint DA, Ju YK, Gage PW. A persistent sodium current in rat ventricular myocytes. J Physiol (Lond) 1992;453:219–
31.PMID: 133451 
39. Wasserstrom JA, Salata JJ. Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes. 
Am J Physiol 1988;254:H1157–66.PMID: 2454585 

Ranolazine in High Risk ICD Patients 
 
 
RAID Protocol Version 6.0 
 
 
 
 
 
 
Page 46 of 47 
September 5, 2014 
40. Zygmunt AC, Eddlestone GT, Thomas GP, et al. Larger late sodium conductance in M cells contributes to electrical 
heterogeneity in canine ventricle. Am J Physiol 2001;281:H689–97.PMID: 11454573 
41. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–
calcium overload. Heart 2006;92 (suppl IV) :iv1–5 
42. Shimizu  , Antzelevitch C. Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in 
the long QT syndrome. J Electrocardiol 1999;32 (Suppl) :177–84.PMID: 10688323 
43. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. 
Circulation 2006;113:2462-72. PMID: 16717165 
44. Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, Greene HL, Boczor S, Domanski M, 
Follmann D, Gent M, Roberts RS. Meta-analysis of the implantable cardioverter defibrillator secondary prevention 
trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study 
Hamburg . Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071-8. PMID: 11102258 
45. Cygankiewicz I, Zareba W, Vazquez R, Vallverdu M, Gonzalez-Juanatey JR, Valdes M, Almendral J, Cinca J, Caminal 
P, de Luna AB; Muerte Subita en Insuficiencia Cardiaca Investigators. Heart rate turbulence predicts all-cause mortality 
and sudden death in congestive heart failure patients. Heart Rhythm 2008;5:1095-102.PMID: 18675217 
46. Wu L, Shryock JC, Song Y, Li Y, Antzelevitch C, Belardinelli L. Antiarrhythmic effects of ranolazine in a guinea pig in 
vitro model of long-QT syndrome. J Pharmacol Exp Ther 2004;310:599–605;  PMID: 15031300  
47. Wu L , Shryock JC, Song Y, Belardinelli L. An increase in late sodium current potentiates the proarrhythmic activities 
of low-risk QT-prolonging drugs in female rabbit hearts. J Pharmacol Exp Ther 2006;316:718–26.PMID: 16234410 
48. Zaniboni M , Pollard AE, Yang L, Spitzer KW. Beat-to-beat repolarization variability in ventricular myocytes and its 
suppression by electrical coupling. Am J Physiol Heart Circ Physiol 2000;278:H677–87.PMID: 10710334 
49. Gralinski MR, BlackSC, KilgoreKS, Chou AY, McCormack JG, Lucchesi BR., et al. Cardioprotective effects of 
ranolazine (RS-43285) in the isolated perfused rabbit heart. Cardiovasc Res 1994;28:1231–7.PMID: 7954626 
50. Frommeyer G, Kaiser D, Uphaus T, Kaese S, Osada N, Rajamani S, Belardinelli L, Breithardt G, Eckardt L, Milberg P. 
Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits. Heart Rhythm 
2012;9:2051-8. 
51. Chaitman BR, Pepine CJ, Parker JO, for the Combination Assessment of Ranolazine In Stable Angina (CARISA) 
Investigators, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina 
frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309–16.PMID: 
14734593 
52. Chaitman BR, Skettino SL, Parker JO, for the MARISA Investigators, et al.Anti-ischemic effects and long-term survival 
during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-82. PMID: 
15093870 
53. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment 
with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006;48:566-575. 
PMID: 16875985 
54. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, 
McCabe CH, Braunwald E; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular 
events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 
2007;297:1775-83. PMID: 17456819 
55. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, Molhoek P, Verheugt FW, Gersh BJ, 
McCabe CH, Braunwald E. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the 
incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the 
Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis 
in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1647-52. PMID: 
17804441 
56. MorrowDA, Scirica BM, Sabatine MS, de Lemos JA, Murphy SA, Jarolim P, Theroux P,  Bode C, Braunwald E. B-type 
Natriuretic Peptide and the Effect of Ranolazine in Patients with Non-ST Elevation Acute Coronary Syndromes in the 
MERLIN-TIMI 36 Trial. Circulation.2007;116:II_382 
57. Fragakis N, Koskinas KC, Katritsis DG, Pagourelias ED, Zografos T, Geleris P. Comparison of effectiveness of 
ranolazine plus amiodarone versus amiodarone alone for conversion of recent-onset atrial fibrillation. Am J Cardiol 
2012;110:673-7 
58. Bunch TJ, Mahapatra S, Murdock D, Molden J, Weiss JP, May HT, Bair TL, Mader KM, Crandall BG, Day JD, Osborn 
JS, Muhlestein JB, Lappe DL, Anderson JL. Ranolazine reduces ventricular tachycardia burden and ICD shocks in 
patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol. 2011;34:1600-6.  
59. Abdallah H, Jerling M. Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-
release tablets. J Clin Pharmacol. 2005; 45: 802–809.PMID: 15951470 
60. Flynn KE, Piña IL, Whellan DJ, Lin L, Blumenthal JA, Ellis SJ, Fine LJ, Howlett JG, Keteyian SJ, Kitzman DW, Kraus 
WE, Miller NH, Schulman KA, Spertus JA, O'Connor CM, Weinfurt KP; HF-ACTION Investigators. Effects of 

Ranolazine in High Risk ICD Patients 
 
 
RAID Protocol Version 6.0 
 
 
 
 
 
 
Page 47 of 47 
September 5, 2014 
exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 
2009;301:1451-9 
61. Chan PS, Soto G, Jones PG, Nallamothu BK, Zhang Z, Weintraub WS, Spertus JA. Patient health status and costs in 
heart failure: insights from the eplerenone post-acute myocardial infarction heart failure efficacy and survival study 
(EPHESUS).Circulation 2009;119:398-407. 
62. Alahdab MT, Mansour IN, Napan S, Stamos TD. Six minute walk test predicts long-term all-cause mortality and heart 
failure rehospitalization in African-American patients hospitalized with acute decompensated heart failure. J Card Fail 
2009;15:130-5. PMID: 19254672 
63. Bank AJ, Kaufman CL, Kelly AS, Burns KV, Adler SW, Rector TS, Goldsmith SR, Olivari MT, Tang C, Nelson L, 
Metzig A; PROMISE-CRT Investigators. Results of the Prospective Minnesota Study of ECHO/TDI in Cardiac 
Resynchronization Therapy (PROMISE-CRT) study. J Card Fail 2009;15:401-9. PMID: 19477400 
64. Brunier HC, Whitehead J.  PEST 3.0 Operating Manual . The University of Reading, Reading, UK, 1993.   
65. Whitehead J.  The Design and Analysis of Sequential Clinical Trials.  Rev’d 2nd ed., John Wiley, New York, 1997. 
66. Hall WJ, Liu A.  Sequential tests and estimators after overrunning based on maximum likelihood ordering. 2002; 
Biometrika 89:699-707. 
67. Lawless JF. Statistical Models and Methods for Lifetime Data. 2nd ed., John Wiley, New York, 2003.  
68. Cook RJ, Lawless JF. The Statistical Analysis of Recurrent Events. Springer, New York, 2007. 
69. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, 
Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, 
Wilson M, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart 
disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and 
Stroke Statistics Subcommittee. Circulation. 2008 Jan 29;117(4):e25-146 
70. Hernandez AF, Fonarow GC, Liang L, Al-Khatib SM, Curtis LH, LaBresh KA, Yancy CW, Albert NM, Peterson 
ED.Sex and racial differences in the use of implantable cardioverter-defibrillators among patients hospitalized with 
heart failure. JAMA. 2007 Oct 3;298(13):1525-32. PMID: 17911497 
71. Dhaliwal AS, Bredikis A, Habib G, Carabello BA, Ramasubbu K, Bozkurt B. Digoxin and clinical outcomes in systolic 
heart failure patients on contemporary background heart failure therapy. Am J Cardiol 2008;102:1356-60. PMID: 
18993155.