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

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

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.

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.

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