Clinical trial NCT01705509
Conditions: Cardiomyopathy
Keywords: The Effects of Ranolazine on CPET Parameters in Ischemic Cardiomyopathy Patients
Sponsor: Cardiovascular Institute of the South Clinical Research Corporation
Start date: 2012-09-01; Completion date: 2017-03-31
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a proof of concept trial using ranolazine, a medication, in patients with known Coronary Artery Disease 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.

Detailed description:
Selected patients will undergo a CPET evaluation. The initial CPET will identify patients with underlying ischemia and serve as a baseline study. Ischemia will be assessed using: 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 peak VO2: estimate stroke volume at those levels of exercise; and 4) the relationship of O2 uptake to work rate (ΔVO2/ΔWR): provides information on the ability of the cardiac output to increase. Patients whoseCPET results meet the criteria for ischemia will be started on Ranexa 500mg BID 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 BID 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 there allotted pill count for the duration of the study. Patients who are found to be noncompliant of less than 80% will be excluded from the study.

Arms: arm 1: All patients who meet the criteria of ischemia will receive ranolazine after enrollment. The initial CPET will serve as the control. The second CPET after 30-days of therapy will serve as the therapy arm. CPET parameters will be assessed and compared both on and off therapy.
Interventions: intervention 1: Ranolazine
Intervention descriptions: intervention 1: The intervention will be ranolazine therapy after the initial 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 BID 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.

Protocol documents:
ICF_000.pdf: 
 
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Cardiovascular Institute of the South 
20121250 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
TITLE:   
The Effects of Ranolazine on CPET Parameters in Ischemic 
Cardiomyopathy Patients (ERIC) 
 
This consent form contains important information to help you decide whether to 
participate in a research study. 
 
 
The study staff will explain this study to you.  Ask questions about anything that is not clear at 
any time.  You can take home an unsigned copy of this consent form to think about and discuss 
with family or friends.   
 
 
 Being in a study is voluntary – your choice. 
 If you join this study, you can still stop at any time. 
 No one can promise that a study will help you. 
 Do not join this study unless all of your questions are answered. 
 
 
After reading and discussing the information in this consent form you should 
know: 
 
 Why this research study is being done; 
 What will happen during the study; 
 Any possible benefits to you; 
 The possible risks to you; 
 Other options you could choose instead of being in this study;  
 How your personal health information will be treated during the study and after the study 
is over; 
 Whether being in this study could involve any cost to you; and 
 What to do if you have problems or questions about this study. 
 
 
Please read this consent form carefully. 


 
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RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
The Effects of Ranolazine on CPET Parameters in Ischemic 
Cardiomyopathy Patients (ERIC) 
 
PROTOCOL NO.: 
None  
 
WIRB® Protocol #20121250 
 
SPONSOR: 
Cardiovascular Institute of the South 
 
INVESTIGATOR: 
Agostino Gus Ingraldi, M.D. 
 
2730 Ambassador Caffery Pkwy 
  
Lafayette, Louisiana 70506 
 
United States 
 
SITE(S): 
Cardiovascular Institute of the South 
 
2730 Ambassador Caffery Parkway 
  
Lafayette, Louisiana 70506 
 
United States 
 
 
Cardiovascular Institute of the South 
 
Suite B 
 
443 Heymann Blvd 
 
Lafayette, Louisiana 70503 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER: 
Agostino Gus Ingraldi, M.D. 
 
Cindy Landry, L.P.N., C.C.R.C. 
 
337-988-1585 (24 hours) 
 
 


 
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Introduction to a research study 
 
We are asking you to be in a research study.  Sometimes research studies are also called clinical 
trials. 
 
The main goal of most research studies is to learn things to help people in the future.   
 
A person who is in a research study is usually called a “subject” (or a “participant” or 
“volunteer”).  A subject has to consent (agree) to be in a research study by signing a consent 
form.   
 
This consent form will help you decide if you want to be a subject in this study.  Please read this 
consent form carefully and completely.  Ask us to explain any words or information that you 
don’t understand. 
 
You can take home an unsigned copy of the consent form so you can think about the study and 
talk to your family and friends before you decide if you want to be in the study. 
 
What you should know before you decide to be in this study 
 
 You will be in the study for about eight weeks (two months). 
 We expect about 50 subjects to be in the study. 
 You don’t have to be in this study.  You can also leave the study without giving a reason. 
 This study might include standard medical treatment or care that is normally given for a 
condition or illness. 
 This study might include an investigational drug or procedure.  “Investigational” means that 
the United States Food and Drug Administration (FDA) hasn’t approved the drug or 
procedure. 
 Before you decide to be in this study, you should know what part of the study (if any) is 
investigational. 
 Your medical or other records might become part of the research record for this study.  If that 
happens, people and groups associated with the study might look at or copy your records. 
 We might bill your health insurance for any standard medical care you receive in this 
study.  Your health insurance might then have access to the research records.   
Your health insurance might not pay for treatment, care, or services that are part of a 
research study.  Being a subject in a research study could also affect your current or 
future health insurance coverage. 
 We will give you a signed and dated copy of this consent form if you decide to be in the 
study. 
 


 
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Why are we doing this study? 
 
Background 
 
Coronary heart disease (CHD) is a leading cause of death and disability in the United States and 
other developed countries.  Close to 18 million people in the U.S. have CHD, and about 
23 million people worldwide have heart failure.  Heart failure has many causes, but the most 
common cause is ischemia from CHD.  “Ischemia” means that a body part such as the heart or 
brain doesn’t get an adequate supply of blood. 
 
Ischemia in heart muscle causes a number of problems.  Eventually the heart doesn’t fill properly 
with blood during the relaxation phase of the heartbeat (called diastole), and this in turn means 
the heart does not have enough blood to pump to the rest of the body. 
 
Study Purpose 
 
We want to study the possible benefits of a drug called Ranexa® (ranolazine) in patients with 
ischemic heart disease by using cardiopulmonary exercise testing (CPET).  CPET measures how 
your lungs and heart work while you exercise on a stationary bike or treadmill.   
 
The United States Food and Drug Administration (FDA) has approved Ranexa® for use in 
patients with coronary artery disease (CAD).  The drug is mainly used to reduce angina 
(chest pain).   
 
Ranexa® is believed to improve relaxation during diastole.  This may reduce the demand for 
oxygen and decrease the oxygen supply-demand mismatch that happens with ischemia.  
Improving this mismatch should make the heart work more efficiently, which in turn will allow 
exercise capacity to increase before symptoms develop. 
 
Unlike a treadmill test alone, CPET measures the exchange of oxygen and carbon dioxide and 
provides a direct assessment of the amount of energy used.  CPET is recognized as the gold 
standard for heart function/exercise capacity testing because it directly measures the amount of 
oxygen inhaled and the amount of carbon dioxide exhaled during exercise. 
 
CPET can accurately assess heart function and detect improvements in function more precisely 
than exercise studies that don’t measure the exchange of oxygen and carbon dioxide.   
 
With this study, we hope to show that:  
 
 Ranexa® will improve heart function that can be objectively assessed with CPET 
 improvement in CPET results with Ranexa® will translate into improved outcomes for 
patients, including improved quality of life 
 


 
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What will happen in the study? 
 
If you decide to be in the study, you will have a CPET evaluation to verify that you have 
ischemia.  This first CPET evaluation will also serve as a baseline for the study. 
 
If this first CPET shows that you qualify for the study, we will start you on 500 mg of Ranexa® 
twice a day.  The next week we will double the dose to 1000 mg twice a day. 
 
After you take the higher dose for four weeks (one month), you will have a second CPET.  We 
will compare the results of the two CPETs to assess any changes that happened while you took 
Ranexa®. 
 
We will call you after you have taken 500 mg for one week and 1000 mg for one week to make 
sure you are tolerating Ranexa® and taking it as directed. 
 
There will be no other changes in medication during the study and no heart procedures.  You will 
have to stop being in the study if you need a medication change or a heart procedure. 
 
At your study visit for the second CPET, we will count the number of Ranexa® tablets to make 
sure you have taken the correct amount.  If you don’t take Ranexa® as directed, you might have 
to stop being in the study. 
 
In addition to measuring improvement in heart function and exercise tolerance, we also want to 
see if you think Ranexa® improves your quality of life.  To do this, we will have you fill out a 
questionnaire. 
 
CPET 
 
During the CPET, you will exercise on either a stationary bike or treadmill. 
 
We will put a number of sticky pads called electrodes on various areas of your chest so that we 
can do an electrocardiogram (EKG) while you exercise.  An EKG measures the heart’s electrical 
activity. 
 
We will also monitor your blood pressure and oxygen with a blood pressure cuff on your arm 
and a small oxygen-measuring device called an oximeter clipped to your finger.  You will also 
wear a mask over your mouth and nose to measure the exchange of oxygen and carbon dioxide.  
 
We will monitor you during the entire exercise test, and emergency drugs and equipment are on 
hand if you have any trouble during the test. 
 


 
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What are your responsibilities during the study? 
 
During the study, we expect you to 
 
 Follow the instructions we give you 
 Store your Ranexa® tablets at room temperature 
 Take Ranexa® as directed (it can be taken with or without meals) 
 Swallow the Ranexa® tablets whole—don’t crush, break, or chew them 
 Let us know if you can’t keep a study appointment or won’t be available for a phone call 
 
For the CPETs 
 
 Don’t eat for two hours before the test 
 Don’t smoke or have caffeine before the test 
 Wear comfortable clothes and shoes for the test 
 
Will being in this study involve risk to you? 
 
The risks for both CPET and Ranexa® are listed and discussed below. 
 
Risks from CPET 
 
The risks from CPET can include  
 
 Irregular heart beat (arrhythmia) 
 Chest pain (angina) 
 Heart attack (myocardial infarction [MI]) 
 Orthopedic injury 
 Death 
 
These risks are generally rare when the test is properly monitored, and emergency equipment and 
drugs are available for problems. 
 
Risks from Ranexa® 
 
Ranexa® can prolong the heart’s QT interval, which is a serious side effect that could lead to 
heart rhythm changes that might be fatal. 
 
The most common side effects of Ranexa® are less serious and include 
 
 Dizziness 
 Headache 
 Constipation 
 Nausea 
 


 
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Other less common side effects reported with Ranexa®  include the following: 
 
 slow heart beat (bradycardia) 
 heart palpitations 
 ringing in the ears (tinnitus) 
 vertigo 
 blurred vision 
 abdominal pain  
 dry mouth 
 vomiting 
 indigestion (dyspepsia) 
 weakness (asthenia) 
 swelling in the arms and legs (peripheral edema) 
 loss of appetite (anorexia) 
 fainting (syncope) 
 confusion 
 blood in the urine (hematuria) 
 trouble breathing; shortness of breath (dyspnea) 
 excessive sweating, especially hands and feet (hyperhidrosis) 
 low blood pressure (hypotension) and a drop in blood pressure when standing after either 
sitting or lying down (orthostatic hypotension), which can cause faintness or dizziness 
 
Other Risks 
 
In this study, we are using Ranexa® for a use other than its FDA-approved use, so there might be 
risks or side effects that we don’t know about yet. 
 
Ask us if you have any questions or want more information about possible risks and side effects. 
 
Will being in this study help you? 
 
Your heart function and exercise tolerance might improve while you are in this study.  But we 
can’t promise this.  We can’t promise that you will have any medical benefit from being in this 
study. 
 
But what we learn from this study might help people with CHD in the future. 
 
Will it cost you to be in this study? 
 
You won’t have any additional costs from being in this study.  The study will pay for both 
Ranexa® and the CPET. 
 
You might have unexpected expenses from being in this research study.  These charges might be 
submitted to your health insurance.  However, your health insurance might not pay these charges 
because you are in a research study.   


 
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In addition, if you are injured as a direct result of being in this study, your insurance company 
might not pay to treat these injuries.   
 
Ask the study doctor to discuss the costs that will or will not be covered by the sponsor.  We also 
encourage you to determine your health insurer’s policy about paying for treatment in a research 
study. 
 
Will you be paid to be in this study? 
 
No, we won’t pay you to be in this study. 
 
What if you are injured or get sick from being in this study? 
 
If you are injured or get sick from being in this study, we will either treat you or refer you for 
treatment. 
 
You or your health insurance will be billed for the cost of any treatment for injury or illness.  
Cardiovascular Institute of the South does not plan to compensate you for any injury or illness or 
for lost time or earnings. 
 
You don’t give up any of your legal rights if you sign this consent form. 
 
What if we learn important new information while you’re in the study? 
 
We will tell you about any new information that might change your decision to be in this study.  
We might ask you to sign a new consent form that includes this information. 
 
What are your options if you decide not to be in this study? 
 
You don’t have to be in this study to receive treatment for CHD.  You also don’t have to be in 
the study to have CPET.  You can have both standard care treatment and CPET for CHD outside 
of the study. 
 
We will talk with you about your other treatment options. 
 
Do you have to be in this study? 
 
No, you don’t have to be in this study.  Being in this study is your choice.  You can decide not to 
be in the study, or you can leave the study at any time.  You don’t have to give a reason.  
Whatever you decide, you won’t be penalized or lose any benefits. 
 


 
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We can also take you out of the study at any time and for any reason without your agreement.  
We might do this if 
 
 We think leaving the study is best for you 
 You don’t agree to stay in the study after we tell you about changes in the study that might 
affect you 
 You don’t take all of the prescribed Ranexa® or you don’t take it as directed 
 You need a change in medication or a heart procedure not allowed by the study 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
 Past and present medical records 
 Research records 
 Records about phone calls made as part of this research 
 Records about your study visits. 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
 working for or with the sponsor, or  
 owned by the sponsor. 
 
Your information may be given to:  
 The U.S. Food and Drug Administration (FDA), 
 Department of Health and Human Services (DHHS) agencies, 
 Governmental agencies in other countries, 
 Cardiovascular Institute of the South 
 Western Institutional Review Board® (WIRB®)  
 
Why will this information be used and/or given to others? 
 to do the research,  
 to study the results, and  
 to make sure that the research was done right.   
 
If the results of this study are made public, information that identifies you will not be used. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 


 
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May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
Yes, but this permission will not stop automatically. 
You may withdraw or take away your permission to use and disclose your health information at 
any time.  You do this by sending written notice to the study doctor.  If you withdraw your 
permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission. 
 
What if you have questions or want more information? 
 
You can ask questions about this study at any time. 
 
You can also call us (Agostino Ingraldi, M.D., or Cindy Landry, L.P.N, C.C.R.C.) at 
337-988-1585 (24 hours) if 
 
 you have questions about this study or your part in it 
 you think you have a research-related injury, problem, or reaction to Ranexa® 
 you have concerns or complaints about this study 
 
You can also contact the Western Institutional Review Board® (WIRB®) if 
 
 you have questions about your rights as a research subject 
 you have questions, concerns, or complaints about this study 
 
WIRB is a group of people who independently reviews research studies in the United States and 
around the world. 
 
WIRB won’t be able to answer some types of questions, such as questions about study appointment 
times.  But you can contact WIRB if you can’t reach the study staff or if you want to talk to 
someone other than the staff. 
 
WIRB’s contact information is listed below: 
 
Western Institutional Review Board® (WIRB®) 
3535 Seventh Avenue SW 
Olympia, Washington 98502 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 


 
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Is there anything else you should know? 
 
 Don’t sign this consent form unless you were able to ask questions and someone answered 
your questions to your satisfaction. 
 
 We will give you a signed and dated copy of this consent form to keep. 
 
My consent to be in the study 
 
My signature on this consent form means that 
 
 I read this consent form (or someone read it to me).   
 The study doctor or study staff answered all my questions about the study and my part in it. 
 I authorize the release of my study and/or medical records to the study doctor, Cardiovascular 
Institute of the South, the FDA, DHHS agencies, government agencies in other countries, and 
WIRB.  
 I don’t give up any of my legal rights by signing this consent form. 
 I agree (consent) to be in this research study. 
 
Consent Instructions 
Consent:  Subjects able to provide consent must sign on the subject line below. 
 
 
________________________________________ 
Subject Name (printed) 
 
 
________________________________________ 
__________________ 
Signature of Subject  
Date 
 


 
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---------------------------- Use this witness section only if applicable ------------------------- 
 
If this consent form is read to the subject because the subject is unable to read the form, an 
impartial witness not affiliated with the research or investigator must be present for the consent 
and sign the following statement: 
 
I confirm that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the subject.   
 
The subject freely consented to be in the research study. 
 
 
________________________________________ 
__________________ 
Signature of Impartial Witness 
Date 
 
Note:  This signature block cannot be used for translations into another language.  A translated 
consent form is necessary for subjects who do not speak English. 


 
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Attestation Statement 
 
I confirm that the research study was thoroughly explained to the subject.  I reviewed the consent 
form with the subject  and answered his or her questions.  The subject  appeared to have 
understood the information and was able to answer the following questions correctly:  
 
1. What is the purpose of this study?  
2. If you decide to be in the study, what will you be asked to do?  
3. What is the possible benefit of participating in this study? 
4. What are the possible risks of participating in this study?  
5. If you decide not to participate in this study, what options do you have?  
6. Will participating in this study cost you anything?  If so, what will you have to pay for?  
7. Do you have to be in this study? 
8. If you decide to be in the study, can you leave the study when you want to?  
 
 
________________________________________ __________________ 
Printed Name of Person Conducting the 
Position 
Informed Consent Discussion 
 
 
________________________________________ __________________ 
Signature of Person Conducting the Informed  
Date 
Consent Discussion 

Prot_001.pdf: 
 
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