The Effects of Ranolazine on CPET Parameters in Ischemic Cardiomyopathy Patients (ERIC)
Phase: NA
Conditions: Cardiomyopathy
Sponsor: Cardiovascular Institute of the South Clinical Research Corporation

 
Title: The Effects of Ranolazine on CPET Parameters in Ischemic  
Cardiomyopathy Patients (ERIC)  
Principle Investigator: Agostino Ingraldi, MD, FACC  
Institution: Cardiovascular Institute of the South  
No Statistical Analysis Plan for this study 
Revised protocol version dated 2/24/2013
NCT01705509 

Title:  The Effects of Ranolazine on CPET Parameters in Ischemic 
Cardiomyopathy Patients (ERIC) 
 
Principle Investigator: Agostino Ingraldi, MD, FACC 
Research Coordinators: Cindy Landry, CCRC and 
Shontel Clevend,CRC  
Institution: Cardiovascular Institute of the South 
 
 
 
 
1. Introduction/Background 
 
Coronary heart disease (CHD) is a leading cause of death and disability in 
developed countries. In 2010 the American Heart Association reported that 17.6 
million persons in the United States have CHD, including 8.5 million with MI and 
10.2 million with angina pectoris (1) Heart failure is estimated to affect 23 million 
persons worldwide (2) and has multiple etiologies; however the most common 
cause of heart failure is ischemia from C HD. 
 
 
Myocardial ischemia has a number of pathophysiologic effects, the earliest of 
which is an increase in the intracellular calcium concentration that results in 
diastolic dysfunction. Intracellular calcium has an affinity for the contractile 
proteins within the myocardial cells and this coupling result in myocardial 
stiffening or diastolic dysfunction. Diastolic dysfunction results in impaired 
cardiac filling or a decrease in preload. This reduction in preload contributes to 
reductions in cardiac output. 
 
 
Ranolazine is an anti-myocardial ischemia with a unique mechanism of action and 
has been shown to reduce angina, nitroglycerine use and increase exercise 
tolerance. It is approved for use in patients with coronary artery disease (CAD) 
(3) The drug decreases the late sodium current at the end of depolarization in the 
cardiac cycle resulting in decreased sodium-calcium overload in the cytoplasm 
(4)This effect is thought to improve myocardial relaxation during diastole in the 
ischemic myocardium resulting in improved energy utilization, thereby reducing 
oxygen demand and decreasing the oxygen supply-demand mismatch during 
ischemia (5) Improving the oxygen supply-demand mismatch should result in 
increased myocardial work efficiency, allowing exercise capacity to increase 
before the onset of symptoms. Improvement in exercise capacity has been 
suggested in previous trials utilizing treadmill stress testing in which changes were 
small and primarily, non-quantitative, without objective data that would allow 
assessment of mechanism of improvement. This proposal is designed to 
quantitatively address the cardiovascular benefits of Ranolazine in patients with 
ischemic heart disease with reduced left ventricular function. 

Evaluating exercise capacity utilizing a treadmill with the Bruce protocol has 
significant limitations and it is difficult to quantitative changes in cardiac function. 
Patients could vary exercise treadmill time (ETT) by holding on to the treadmill 
rails to a lesser or greater degree. Therefore this method does not estimate 
unsupported exercise capacity and does not accurately translate into metabolic cost 
of the work performed at the time the patient stops exercise from symptoms. The 
ETT does not accurately reflect work capacity or peak VO2. Cardiopulmonary 
exercise testing (CPET) measures gas exchange and provides a direct assessment 
of energy expenditure equivalents of both the aerobic and anaerobic types. It is 
recognized in the medical literature as the GOLD standard for functional/exercise 
capacity assessments because it directly measures O2 uptake and also concurrent 
CO2 output from buffering of  lactic acid accumulation secondary to anaerobic 
metabolism during exercise. Specifically, as noted in the next paragraph, the 
following determinations can be made from each test: 1) peak VO2 : measures the 
peak transport of O2 to the tissues when O2 extraction from the blood is maximal; 
2) The anaerobic threshold (AT): measures the sustainable work capacity in units 
of VO2;  3) the O2-pulse measurements at the AT and peak VO2: estimate stroke 
volume at those levels of exercise; and 4) the relationship of O2 uptake to work 
rate ( VO2/ WR): pro vides in formation on the ability of the cardiac output to 
increase appropriately for the work rate increase. 
 
CPET can accurately assess cardiac function and elucidate u n d e r l y i n g  
mechanisms of cardiac dysfunction. It can also be detect improvements in cardiac 
function more precisely than exercise studies without gas exchange measurements. 
In ischemia evaluations, the work rate is gradually increased so that the patient’s 
maximum work capacity is reached in approximately 10 minutes. If a patient has 
underlying C AD, so that the myocardium does not receive the O2 needed to 
maintain myocardial contraction at a specific heart rate or double product, that 
portion of the myocardium that is ischemic will stop contracting normally. The 
physiological explanation for why the ischemic portion of the myocardium cannot 
contract is the failure to regenerate the O2 supported high-energy phosphate 
needed to maintain myocardial contraction. Thus, myocardial hypokinesis will 
develop at and above the ischemic threshold during the course of the stress test. 
This causes stroke volume to decrease while heart rate increases faster relative to 
VO2 in partial compensation, presumably stimulated by tissue hypoxia. Reflecting 
the failure to maintain the cardiac output increase appropriate for the work rate 
increase is a decrease in VO2/ WR below 10 ml/min/watt, the normal slope below 
the ischemic threshold, as described by Belardinelli et al. (6), Contini et al (7), 
Klainman et al (8), and Itoh et al (9) From the Fick principle [VO2 = HR X 
SV X C(a-v)O2], where HR = heart rate, SV = stroke volume, and C(a-v)O2 = O2 
content difference between arterial and mixed venous blood, and the O2-pulse = 
VO2/HR = SV X C(a-v)O2. Failure for cardiac output to increase appropriately 
can be seen by the decreasing rate of rise in VO2 relative to work rate increase. 

Reflecting the tissue hypoxia brought on by the myocardial ischemia is the 
maintained steep rise in VCO2 arising out of HCO3- buffering of the newly formed 
lactic acid. Since the onset of myocardial ischemia and hypokinesis results in a 
decrease in stroke volume at the ischemic threshold, a low and flattened O2- pulse, 
or a decreasing rather than the normally increasing O2-pulse, can be identified. 
Furthermore, immediately following peak exercise in the patient with myocardial 
ischemia, the O2-pulse often increases in the immediate recovery period, reflecting 
an increase in stroke volume due to the abrupt decrease in after- load of the heart 
when systolic pressure, heart rate and double product decrease at the start of 
recovery. This post-exercise increase in O2-pulse is not seen in normal subjects. 
Two clinical trials have shown that the sensitivity of CPET to detect exercise 
induced ischemia by the above criteria is in the mid to upper 80% range (6,9). The 
technique can also be used to demonstrate physiological improvement after therapy 
(7,8). In patients with a definable ischemic threshold demonstrated 
by a flattening of the VO2/ WR relationship, treatment with Ranolazine, if it 
improves myocardial blood flow and/or decreases the myocardial O2 requirement, 
might : 1) increase the work rate and VO2 at which  VO2/ WR becomes abnormally 
shallow 2) reduce the flattening of  VO2 / WR, increasing it toward 
the normal 10 ml/min/watt; 3) increase the peak O2-pulse and 4) increase the heart 
rate and work rate at which the O2-pulse reaches its maximum. If Ranolazine 
improves diastolic relaxation and thereby improves cardiac output during exercise, 
CPET should reveal an increase in peak O2-pulse in proportion to the increase in 
peak stroke volume. This will likely translate into improve cardiac outcomes in 
this patient population. 
 
2. Hypothesis 
 
This is a proof of concept trial using Ranolazine in patients with known CAD and 
reduced left ventricular function, EF  < 40%. We propose that Ranolazine therapy 
will result in demonstrative improvements in cardiac function that can be 
objectively assessed using the parameters measured with CPET. We propose that 
demonstrative improvement in CPET parameters on Ranolazine will translate into 
improved patient outcomes for this patient population. 
 
3. Study Design 
 
Selected patients will undergo a CPET evaluation. Beta Blockers will be held day 
prior to and day of CPET. The initial CPET will identify patients with underlying 
ischemia and serve as a baseline study. Patients whose CPET results meet the 
criteria for ischemia will be started on Ranexa 500mg B ID and advanced within 
one week +/-4 days to 1000mg  BID. A second CPET will be performed after 4 
weeks +/- 4 days of maximum therapy. CPET results before and after therapy will 
undergo a statistical comparison. The initial off treatment CPET measurement will 
serve as the control to assess changes found during therapy.  No medication 
changes or revascularization procedures will occur during the study. 

If patients require and undergo a medication change or a revascularization 
procedure, they will be excluded from the study. 
 
Patients will be contacted at the completion of week one prior to up titration, then 
at the end of week two to ensure tolerance and compliance with the 1000mg B ID 
dose. Patients will perform the second CPET study at week four +/- 1 week. The 
trial medication will be assessed and counted to ensure that patients have taken 
their allotted  pill count for the duration of the study. Patients who are found to be 
noncompliant  will be excluded from the study. 
 
4. Endpoints 
 
Endpoints will include changes in CPET parameters, cardiac output and stroke 
volume. Additional endpoints will include changes in quality of life scores (QOL) 
as measured Seattle Angina Cardiomyopathy Questionnaire. ST-segment will be 
assessed for changes and the timing of onset. 
 
 
5. Study Population 
 
Up to Fifty patients will be enrolled in the trial. Patient will be selected by chart 
review and physician recommendation. 
 
Inclusion Criteria 
 
1.  Patients > 18 years of age will be enrolled in the trial. 
2.  Stable patients without hospitalizations, medication changes or cardiac 
intervention within two weeks of the study will be enrolled. 
3.  Patients must be able to complete the CPET protocol and must have 
demonstrable ischemia on the initial CPET evaluation. 
4.  Patients must have a documented ejection fraction  < 40% 
a. L V  function can be assessed via: 
i.  Echocardiogram 
ii.   MUGA or Nuclear Perfusion Scan 
iii.   Left ventriculogram 
5.  Patients must be Ranexa naive and without contraindication for Ranexa 
Therapy. 
 
Exclusion Criteria 
 
1.  QTc>500 msec on restin g EKG 
2.  Chirosis of the Liver 
3.  Have received prior treatment with ranolazine 

 
4.  Treatment with potent CYP3A inhibitors and, HIV protease inhibitors or 
consumption of more than eight ounces of grapefruit juice or grapefruit 
juice containing products 
5.  Have participated in another trial of an investigational device or drug within 30 
days of screening 
6.  Have end stage renal disease requiring dialysis 
7.  Have any chronic illness likely to affect compliance with the protocol 
8.  Have second or third degree atrioventricular block in the absence of a 
functioning ventricular pacemaker 
 9. Have uncontrolled clinically significant cardiac arrhythmias, or a history of 
ventricular fibrillation, torsade de pointes, or other life-threatening ventricular 
arrhythmias 
10. Uncontrolled HTN defined as BP > /= 160/100 mm Hg at three consecutive visits. 
 
 
 
6. Informed Consent 
 
All study subjects must provide written informed consent using the applicable IRB 
approved informed consent form. Each patient must receive a copy of his/her 
signed consent form. The original signed consent document must be kept on file at 
the investigative site. The study must be explained in a language that is 
understandable to the patient and he/she must be allowed sufficient time to decide 
whether to participate in this study. All subjects will be assured that they have the 
right to withdraw from the study at any time during the course of the protocol and 
this decision will not influence his/her relationship with the lead investigator, the 
treating physician and/or the study staff. 
 
7. Monitoring and Reporting of Adverse Reaction 
 
It will be the responsibility of the research site to monitor all adverse events (AE). 
Information regarding all reportable AE’s will be reported in accordance to IRB 
reporting guidelines. 
 
 
8. Institutions Review Board 
 
A copy of the protocol and HIPAA waiver must be submitted to the institution's 
IRB for written approval. No recruitment/activities will occur until such IRB 
approval had been granted in writing. The Cardiovascular Institute of the South 
must receive a copy of the written IRB approval of the protocol before the study is 
initiated. 

The site investigator must submit and, where necessary, obtain IRB approval for 
all protocol amendments. The investigator must notify the IRB of protocol 
violations. 
 
9. Record Retention 
 
The site will retain all source documentation that support the data collected on the 
study patients in compliance with ICH/GCP guidelines. Documents must be 
retained for at least 2 years after the study completion. The investigator must 
accept responsibility for ensuring that study documents are not damaged or 
destroyed. Each patient’s study data will be collected and will be securely stored 
in the site’s offices. Patients will be identified using a study identification number. 
Patient information will be de-identified for data analysis. 
 
10. Study Finances 
 
This study is financed through an unrestricted grant by Gilead, Inc. 333 Lakeside 
Drive Foster City, CA 94404 USA. 
 
11. Payment 
 
The patients do not receive any payment to be part of the study. Otherwise, they 
will receive standard medical care, except for what is stipulated in the protocol. 
 
12. Study Medication 
 
Ranolazine is FDA approved for the treatment of chronic Angina. It may be taken 
with or without meals.  Swallow tablets whole, do not crush, break, or chew. 
Ranolazine tablets should be stored at room temperature between 59°-86°F (15°- 
30°C).  Possible serious side effect s are QT prolongation. Most common side 
effects are dizziness, headache, constipation, and nausea. 
 
13. Study Duration 
 
Total anticipated length of individual’s participation: Approximately 8 weeks. 
 
14. Endpoints 
 
Endpoints will include changes in CPET parameters, cardiac output and stroke 
volume. Additional endpoints will include changes in quality of life scores (QOL) 
as measured Seattle Angina Cardiomyopathy Questionnaires. ST segment changes 
and the timing of onset will be assessed. 

 
 
Reference: 
 
1.  Lloyd-Jones et al Executive summary: heart disease and stroke statistics-- 
2010 update: a report from the American Heart Association. 
 
 
2.  Clinical epidemiology of heart failure: public and private health 
burden. McMurray JJ, Petrie MC, Murdoch DR, Davie AP Eur Heart J. 
1998;19 Suppl P:P9.) 
 
 
3.  Wenger NK, Chaitman B, Vetrovec GW. Gender comparison of efficacy 
and safety of Ranolazine for chronic angina pectoris in four randomized 
clinical trials. Am J Cardiol 2007;99: 11-18. 
 
 
4.  Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current 
as a potential cardioprotective principle: effects of the late sodium current 
inhibitor ranolazine. Heart 2006;92(Suppl IV):iv6-iv14. 
 
 
5.  Chaitman B. Ranolazine for the treatment of chronic angina and potential 
use in other cardiovascular conditions. Circulation 2006;113:2462-2472. 
 
 
6.  Bellardinelli B, et al. Exercise induced myocardial ischemia detected by 
cardiopulmonary exercise testing. European Heart Journal (2003); 24; 
1304-1313. 
 
 
7.  Contini M, et al. Cardiopulmonary exercise test evidence of isolated right 
coronary artery disease. International Journal of Cardiology 2005.09.033. 
 
 
8.  Klainman E, et al. Assessment of functional results after percutaneous 
transluminal coronary angioplasty by cardiopulmonary exercise test. 
Cardiology 1998; 89:257-262. 
 
 
9. Itoh, H et al. Oxygen uptake abnormalities during exercise in coronary artery 
disease. In Cardiopulmonary Exercise Testing and Cardiovascular Health. 
Edited by K. Wasserman, Published by Futura Publishing Company, Armonk 
NY, 2002. 
 
 
 
 
 
 
Revised protocol version dated 2/24/2013