Effectiveness of Stem Cell Treatment for Adults With Ischemic Cardiomyopathy (The FOCUS Study)

Study Overview
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Brief Summary
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Coronary artery disease (CAD) is a common disorder that can lead to heart failure. Not all people with CAD are eligible for today's standard treatments. One new treatment approach uses stem cells-specialized cells capable of developing into other types of cells-to stimulate growth of new blood vessels for the heart. This study will determine the safety and effectiveness of withdrawing stem cells from someone's bone marrow and injecting those cells into the person's heart as a way of treating people with CAD and heart failure.

Detailed Description
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Coronary artery disease (CAD), a disease in which blood vessels become clogged by a build-up of plaque, is the leading cause of heart failure, a condition in which the heart can no longer pump enough blood to the rest of the body. People with heart failure caused by CAD are said to have ischemic cardiomyopathy. Normal treatment for CAD involves coronary artery bypass grafting (in which a vein from another part of the body is grafted around an artery that has become blocked) or coronary angioplasty and stent placement (in which a blocked artery is opened and a small tube is placed to keep the artery open). However, some people with ischemic cardiomyopathy, such as those with substantial scar tissue on the heart wall or those with a particular heart structure, may not be eligible for these treatments. An alternative treatment being developed is therapeutic angiogenesis, which involves stimulating the growth of new blood vessels. Recent research has shown that withdrawing stem cells from bone marrow and implanting the cells into heart tissue may be an effective way to achieve therapeutic angiogenesis. This study will determine the safety and effectiveness of using stem cells to stimulate new blood vessel growth in the hearts of people with ischemic cardiomyopathy. Participation in this study, including follow-up visits and phone calls, will last 60 months. Participants will first undergo 3 to 4 days of screening procedures that will include a physical examination, multiple lab tests, and a battery of tests on heart health. Next, participants will be randomized to receive either active stem cell injections or placebo injections. The injections and related procedures will be performed in a hospital and last approximately 72 hours. During this time, participants in both groups will first undergo a bone marrow aspiration procedure. Participants receiving active stem cells will also undergo NOGA electromechanical cardiac mapping, which involves inserting a monitoring device through a catheter and into the heart. Injections of stem cells will then be made to 15 damaged sites on the heart through a special catheter. Participants receiving placebo injections will receive 15 injections of an inactive, saline-based solution. After the injection procedures, all participants will undergo two echocardiograms, an electrocardiogram, blood tests, and overnight monitoring in a telemetry unit. After the hospital stay, all participants will attend five study visits that will occur 1 week and 1, 3, 6, and 12 months after the injection procedures. At all study visits, participants will undergo an electrocardiogram, lab tests, and a review of adverse health events. On all but the last study visit, participants will have cardiac markers assessed, and they will wear a 24-hour Holter monitor to track heart activity. At the last three visits, participants will also complete quality of life questionnaires. All participants will then receive four follow-up telephone calls that will occur 2, 3, 4, and 5 years after the injection procedures.

Official Title
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Randomized, Controlled, Phase II, Double-Blind Trial of Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells Under Electromechanical Guidance for Patients With Chronic Ischemic Heart Disease and Left Ventricular Dysfunction

Conditions
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Chronic Ischemic Heart Disease, Left Ventricular Dysfunction, Angina, Ischemic Cardiomyopathy

Intervention / Treatment
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* Biological: Adult stem cells
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients >18 years of age with significant coronary heart disease not amenable to revascularization. Left ventricular dysfunction (LVEF) less than or equal to 45%, measured by echocardiogram; limiting angina (Class II to IV); and/or congestive heart failure (CHF), NYHA class II to III Receiving maximal medical therapy, defined as a medical regimen that includes the maximal tolerated dose of at least two antiangina medications, such as beta-blockers, nitrates, or calcium-channel blockers Presence of a defect, as identified by single photon emission computed tomography (SPECT) isotope protocol, or viability, as identified by NOGA electromechanical cardiac mapping system Coronary artery disease not well suited to any other type of revascularization procedure in the target region of the ventricle, as determined by a cardiovascular surgeon and interventional cardiologist who are not investigators in the trial Hemodynamic stability, as defined by systolic blood pressure of at least 80 mm Hg without intravenous pressors or support devices Females of childbearing potential must be willing to use two forms of birth control for the duration of the study Exclusion Criteria: Atrial fibrillation or flutter without a pacemaker that guarantees a stable heart rate Unstable angina Left ventricular (LV) thrombus, as documented by echocardiography or LV angiography A vascular anatomy that precludes cardiac catheterization Severe valvular disease or mechanical aortic valve that precludes safe entry of the catheter into the left ventricle Pregnant or lactating Platelet count less than 100,000 per mm3 White blood cell count less than 2,000 per mm3 Revascularization within 30 days of consent Transient ischemic attack or stroke within 60 days of study consent Implantable cardioverter-defibrillator shock within 30 days of baseline consent, and within 30 days of randomization Presence of ventricular tachycardia lasting 30 seconds or more on 24-hour Holter monitor or electrocardiogram (ECG) performed during screening period Bleeding diathesis, defined as an international normalized ratio of at least 2.0 in the absence of warfarin therapy A history of malignancy in the last 5 years excluding basal cell carcinoma, that has been surgically removed, with proof of surgical clean margins Has a known history of HIV, has active hepatitis B or active hepatitis C Any condition requiring immunosuppressive medication High-risk acute coronary syndrome (ACS) or a myocardial infarction in the month prior to consent A left ventricular wall thickness of <8 mm (by echocardiogram) of the infero-lateral wall at the target site for cell injection. Inability to walk on a treadmill, except for class IV angina patients, who will be evaluated separately Enrolled in an investigational device or drug study within the previous 30 days Hepatic dysfunction, as defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal range prior to study entry Chronic renal insufficiency, defined as a serum creatinine level greater than 2.5 mg/dL or requiring dialysis Any other condition that in the judgment of the investigator would be a contraindication to enrollment or follow-up

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Injections<br>Participants will receive placebo injections. | Biological: Placebo<br>* Single procedure of intramyocardial electromechanical-guided needle insertions and injection of 5% human serum albumin and saline in 15 different injection sites<br>* Other names: HSA;|
| Experimental: Active Stem Cell Injections<br>Participants will receive active stem cell injections. | Biological: Adult stem cells<br>* Single procedure of intramyocardial electromechanical-guided injection of approximately 100 million bone marrow mononucleated cells (BM-MNCs), administered in 15 different injection sites<br>* Other names: Bone marrow mononucleated cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Maximal Oxygen Consumption (VO2max) | The VO2(max) is assessed using the Naughton treadmill protocol. | Measured at Baseline and Month 6 | 
| Change in Left Ventricular End Systolic Volume (LVESV)as Assessed Via Echo | Echocardiographic measurements were performed by an echocardiographic core laboratory. LVESVs were calculated by the modified biplane Simpson method, using myocardial contrast to enhance endocardial definition. To account for patient body surface area, LVESV indices are reported. | Measured at Baseline and Month 6 | 
| Change in Reversible Defect Size | Adenosine myocardial perfusion (SPECT) tests were collected at baseline and 6 months to identify change in ischemic (reversible) defects. SPECT imaging was performed at rest and after adenosine infusion over 4 minutes. To enhance the detection of viability on resting images, sublingual nitroglycerin was administered 15 minutes before injecting technetium Tc 99m sestamibi for the resting image. | Measured at Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regional Wall Motion by MRI (in Eligible Patients) | Regional wall motion as measured by cardiac MRI (in patients who are not contraindicated) | Measured at Baseline and Month 6 | 
| Regional Blood Flow Improvement by MRI (in Eligible Patients) | Regional blood flow improvement as measured by cardiac MRI (in patients who are not contraindicated) | Measured at Baseline and Month 6 | 
| Regional Wall Motion by Echocardiography | Movement of the left ventricular wall measured in mm from baseline to six months. | Measured at Baseline and Month 6 | 
| Clinical Improvement in CCS Classification (Angina Pectoris) | Clinical improvement in Canadian Cardiovascular Society (CCS) functional classification of angina pectoris. The CCS scale ranges from Class I (best)able to conduct ordinary daily activity without causing angina to Class IV (worst) Inability to perform any physical activity without discomfort; anginal symptoms may be present at rest. Patients receive a rating of 1-4 for their anginal symptoms. Results reflect the mean change in the total score over time. | Measured at Baseline and Month 6 | 
| Clinical Improvement in NYHA Classification | Clinical improvement in New York Heart Association (NYHA) classification. The NYHA scale ranges from 1 (best)Mild- no limitation of physical activity due to heart failure to 4 (worst) Severe-Unable to carry out any physical activity without discomfort due to heart failure. Patients receive a rating of 1-4 for their heart failure symptoms. Results reflect the mean change in the total score over time. | Measured at Baseline and Month 6 | 
| Number of Participants With a Decrease in Anti-anginal Medication | Number of participants with a decrease in anti-anginal medication (nitrates needed weekly) | Measured at Baseline and Month 6 | 
| Exercise Time and Level | Exercise time and level as assessed via six minute walk test. (change in number of feet walked) | Measured at Baseline and Month 6 | 
| Serum BNP Levels in Patients With CHF | Serum b-type natriuretic peptide (BNP) levels in patients with congestive heart failure (CHF). A minority number of patients had pro-BNP collected versus regular BNP; these numbers are reported in the analysis population description. | Measured at Baseline and Month 6 | 
| LV Diastolic Dimension | Left ventricular (LV) diastolic dimension as assessed by contrast echocardiography | Measured at Baseline and Month 6 | 
| Incidence of a Major Adverse Cardiac Event | Incidence of major adverse cardiac events (new MI, rehospitalization for PCI in coronary artery territories that were treated, death, or rehospitalization for acute coronary syndrome and for congestive heart failure). (Incidence rate) | Measured at Baseline and Month 6 | 
| Reduction in Fixed Perfusion Defect(s)Via SPECT | Fixed total defect is the stress total defect minus the reversible component. | Measured at Baseline and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congestive Heart Failure, Regional Wall Motion, Perfusion Defects