Cardiovascular Cell Therapy Research Network (CCTRN) 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 (FOCUS)
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March 2009-May 2012
August 26, 2019
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Data Restrictions Based On Area Of Research No
To evaluate the efficacy of transendocardial-delivered autologous bone marrow mononuclear cells (BMCs) in patients with chronic ischemic heart disease and left ventricular dysfunction with heart failure and/or angina.
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. Normal treatments for CAD involves coronary artery bypass grafting, or coronary angioplasty and stent placement; however, some people may not be eligible for these procedures. 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.
Initial studies- including a pilot study in Brazil and a phase I trial of autologous BMC therapy in heart failure (FOCUS-HF)-have shown that transendocardial delivery of BMCs appeared safe in patients with chronic heart failure due to multi-vessel coronary artery disease, but definitive assessments of efficacy were not evaluated due to insufficient enrollment numbers. The FOCUS-CCTRN was designed to investigate the efficacy of specific measures such as left ventricular (LV) function, perfusion, and functional capacity in autologous cell therapy of patient with ischemic heart disease.
273 patients were assessed for eligibility. Of these, only 92 patients were randomized. 61 patients were randomized to the treatment arm and 31 patients were randomized to the placebo arm.
Eligible patients for this trial were male and female adult patients (>18 years of age) with significant coronary heart disease not amenable to revascularization in the target region of the ventricle, which was determined by a cardiovascular surgeon and intervention cardiologist unaffiliated with the trial. Additional eligibility requirements included: 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; presence of a defect, as identified by single photon emission computed tomography (SPECT) isotope protocol; hemodynamic stability, defined as systolic blood pressure of ≥80 mm Hg with intervention/support devices.
Selected exclusion criteria included: unstable angina, left ventricular thrombus, vascular anatomy that precludes cardiac catheterization, pregnant or lactating, platelet count ≤100,000/mm3, WBC count ≤2,000/mm3 , a known history of HIV, active hepatitis B or active hepatitis C, and any other condition that in the judgement of the investigator would be a contraindication to enrollment or follow-up.
FOCUS-CCTRN was a randomized, phase II, double-blind, placebo-controlled trial designed to determine whether transendocardial administration of 100 x 106 BMC improves measures of LV performance and perfusion at 6 months compared with baseline levels.
Eligible participants were randomized in a 2:1 ratio to receive either BMCs or placebo (cell-free) preparation using computer-generated variable block sizes of 6 or 9, randomly selected and stratified by center. All randomized patients underwent baseline testing, bone marrow harvest, and automated cell processing, which was performed locally.
The target dose for the BMC treatment group was 100 x 106 total BMCs. The BMC final product was suspended in normal saline containing 5% human serum albumin and adjusted to a concentration of 100 x 106 cells in 3 mL distributed in (3)- 1mL syringes. The placebo group received a cell-free suspension in the same volume.
The treatments were delivered within 12 hours of bone marrow aspiration in 15 separate injections (0.2mL each) to left ventricular endocardial regions identified as viable by electromechanical mapping (EMM). A 2-dimensional echocardiogram was performed immediately after the procedure and on the next day before discharge. Serial measurements of biomarkers (CK, CK-MB, and troponin) were obtained. All patients remained in the hospital overnight and discharged with guideline-recommended therapy.
Patients were examined for safety and efficacy at 6 months using three pre-specified primary endpoints- LVESV, MV02, and change in SPECT defect size. LVESV, left ventricular end-systolic volume, was evaluated by echocardiographic measures. MV02, maximal oxygen consumption, was assessed using the Naughton treadmill protocol. Adenosine myocardial perfusion tests were performed with single-photon emission tomography (SPECT) to identify changes in ischemic defects from rest and after adenosine infusion using standardized protocols.
Further follow-up for safety was continued for up to 12 months and annual phone calls were scheduled for 2, 3, 4, and 5 years post-intervention.
There was no significant difference in the primary outcome between the treatment and placebo groups. In patients with chronic ischemic heart disease, transendocardial injection of BMCs compared to placebo did not improve LVESV, MV02, or reversibility in SPECT.
Perin EC, Willerson JT, Pepine CJ, et al. 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 [published correction appears in JAMA. 2015 Jul 7;314(1):86]. JAMA. 2012;307(16):1717–1726. doi:10.1001/jama.2012.418
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