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.

Study Overview

• Status: Completed
• Conditions: Ischemic Cardiomyopathy; Left Ventricular Dysfunction; Angina; Chronic Ischemic Heart Disease
• Intervention / Treatment: Biological: Placebo; Biological: Adult stem cells

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida-Department of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77225
      • Texas Heart Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Cardiovascular Cell Therapy Research Network (CCTRN)

Publications and helpful links

General Publications

• Gee AP, Richman S, Durett A, McKenna D, Traverse J, Henry T, Fisk D, Pepine C, Bloom J, Willerson J, Prater K, Zhao D, Koc JR, Ellis S, Taylor D, Cogle C, Moye L, Simari R, Skarlatos S. Multicenter cell processing for cardiovascular regenerative medicine applications: the Cardiovascular Cell Therapy Research Network (CCTRN) experience. Cytotherapy. 2010 Sep;12(5):684-91. doi: 10.3109/14653249.2010.487900.
• Willerson JT, Perin EC, Ellis SG, Pepine CJ, Henry TD, Zhao DX, Lai D, Penn MS, Byrne BJ, Silva G, Gee A, Traverse JH, Hatzopoulos AK, Forder JR, Martin D, Kronenberg M, Taylor DA, Cogle CR, Baraniuk S, Westbrook L, Sayre SL, Vojvodic RW, Gordon DJ, Skarlatos SI, Moye LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design. Am Heart J. 2010 Aug;160(2):215-23. doi: 10.1016/j.ahj.2010.03.029.
• Zierold C, Carlson MA, Obodo UC, Wise E, Piazza VA, Meeks MW, Vojvodic RW, Baraniuk S, Henry TD, Gee AP, Ellis SG, Moye LA, Pepine CJ, Cogle CR, Taylor DA. Developing mechanistic insights into cardiovascular cell therapy: Cardiovascular Cell Therapy Research Network Biorepository Core Laboratory rationale. Am Heart J. 2011 Dec;162(6):973-80. doi: 10.1016/j.ahj.2011.05.024.
• Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012 Apr 25;307(16):1717-26. doi: 10.1001/jama.2012.418. Epub 2012 Mar 24. Erratum In: JAMA. 2015 Jul 7;314(1):86.
• Cogle CR, Wise E, Meacham AM, Zierold C, Traverse JH, Henry TD, Perin EC, Willerson JT, Ellis SG, Carlson M, Zhao DX, Bolli R, Cooke JP, Anwaruddin S, Bhatnagar A, da Graca Cabreira-Hansen M, Grant MB, Lai D, Moye L, Ebert RF, Olson RE, Sayre SL, Schulman IH, Bosse RC, Scott EW, Simari RD, Pepine CJ, Taylor DA; Cardiovascular Cell Therapy Research Network (CCTRN). Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes. Circ Res. 2014 Oct 24;115(10):867-74. doi: 10.1161/CIRCRESAHA.115.304353. Epub 2014 Aug 18.

Helpful Links

• Click here for more information on the Cardiovascular Cell Therapy Research Network
• Click here for more information on the National Heart, Lung, and Blood Institute

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: January 15, 2009
• First Submitted That Met QC Criteria: January 15, 2009
• First Posted (Estimate): January 16, 2009

Study Record Updates

• Last Update Posted (Estimate): July 1, 2015
• Last Update Submitted That Met QC Criteria: June 2, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Congestive Heart Failure; Regional Wall Motion; Perfusion Defects
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Ischemia; Cardiomyopathies; Ventricular Dysfunction; Ventricular Dysfunction, Left
• Other Study ID Numbers: 580; U01HL087318 (NIH); 1 U01-HL-087318-01 (Project 3)