Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS)

Study Overview
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Brief Summary
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Heart attacks are a leading cause of death in both men and women in the United States. When a person has a heart attack, blood is unable to reach a certain area of the heart, and if the blood supply is not re-established quickly, that area of the heart can suffer permanent damage. While recovery from a heart attack can be managed through medications and lifestyle changes, these treatments can not reverse the original damage to the heart. Current research is focusing on the development of cell-based therapies using stem cells to repair organs that have been irreversibly damaged by disease. A specific form of stem cells, called adult mesenchymal stem cells (MSCs), has shown promise for heart repair. This study will evaluate the safety and effectiveness of injecting MSCs into the heart to repair and restore heart function in people who have had a heart attack and who are having heart surgery for coronary artery bypass grafting (CABG).

Detailed Description
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Participation in this study will last 18 months. Potential participants will undergo initial screening 5 to 7 weeks prior to CABG surgery. Screening will include a physical exam, blood draw, pregnancy test, questions about medical history, current medications, and alcohol or drug use, an electrocardiogram (ECG), magnetic resonance imaging (MRI) of the heart, questionnaires, an echocardiogram and a computed tomography (CT) scan. Eligible participants will then undergo two baseline visits within 6 weeks of their scheduled surgery. Baseline Visit 1 will consist of vital sign measurements, a bone marrow aspiration to obtain MSCs and a blood draw for a biomarker test. Baseline Visit 2 will include treadmill test, 6-minute walk test, pulmonary function (FEV1) study and a 48 Hour Ambulatory ECG. After the second baseline visit, participants will be assigned randomly to receive either MSCs or placebo after surgery. On the day of surgery, once all of the bypass grafts have been placed, a high or low dose of MSCs or placebo will be injected into a damaged area of the heart that did not receive a bypass graft. After receiving the injections, participants will remain in the hospital for up to 7 days. During this stay, participants will undergo a daily blood draw, urine test, ECG, and ambulatory ECG monitoring for the first 96 hours after surgery. Upon being discharged, participants will return for monthly visits for 6 months and for follow-up visits 12 and 18 months after surgery. These visits will repeat most initial screening and baseline tests. There will be one additional visit 14 days after surgery, which will include questions about side effects, a physical exam, and a 48-hour ambulatory ECG.

Official Title
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A Phase I/II, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Intramyocardial Injection of Autologous Human Mesenchymal Stem Cells (MSCs) in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction (MI) Undergoing Cardiac Surgery for Coronary Artery Bypass Grafting (CABG)

Conditions
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Stem Cell Transplantation, Ventricular Dysfunction, Left

Intervention / Treatment
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* Biological: Lower dose mesenchymal stem cell (MSC) injection
* Genetic: Placebo
* Biological: Higher dose MSC injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic ischemic heart failure caused by a heart attack Scheduled to undergo cardiac surgery for CABG Ejection fraction between 15% and 50% Presence of an akinetic or dyskinetic region by standard imaging Exclusion Criteria: Glomerular filtration rate of less than 50 mL/min/1.73m2 at study entry Contraindication to performance of an MRI scan Bone marrow dysfunction, as evidenced by a 20% or more deviation from normal hematocrit, white blood cell count, or platelet values without another explanation A coagulopathy condition not due to a reversible cause (i.e., Coumadin) Known, serious radiographic contrast allergy Known allergies to penicillin or streptomycin Organ transplant recipient Clinical history of malignancy within 5 years of study entry (e.g., patients with prior malignancy must be disease free for 5 years), except curatively treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma Non-cardiac condition that limits lifespan to less than 1 year On chronic therapy with immunosuppressant medication Serum positive for HIV, hepatitis B, or hepatitis C Female who is pregnant, nursing, or of child-bearing potential and not practicing effective birth control methods

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lower dose mesenchymal stem cell (MSC) injection<br>Participants will receive lower dose mesenchymal stem cell injections for a total of 2 x 10^7 cells | Biological: Lower dose mesenchymal stem cell (MSC) injection<br>* Participants will receive between 10 and 20 intramyocardial injections of 2 million MSCs per 0.25-0.5 cubic centimeter (cc) for a total of 2 x 10^7 cells. The injections will be administered following completion of CABG surgery.<br>|
| Experimental: Higher dose MSC injection<br>Participants will receive higher dose of mesenchymal stem cell injections for a total of 2 x 10^8 cells | Biological: Higher dose MSC injection<br>* Participants will receive between 10 and 20 intramyocardial injections of 20 million MSCs per 0.25-0.5 cc for a total of 2 x 10^8 cells. The injections will be administered following completion of CABG surgery.<br>|
| Placebo Comparator: (3) Placebo<br>Participants will receive placebo injections | Genetic: Placebo<br>* Participants will receive between 10 and 20 placebo injections that consist of phosphate buffered saline (PBS) and 1% human serum albumin (HSA).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Serious Adverse Events | Six-month post-CABG surgery serious adverse event (SAE) proportion of patients experiencing a composite of sustained ventricular arrhythmias, (lasting longer than 15 seconds), with hemodynamic compromise, sudden unexpected death at six months, ectopic tissue formation at 12 months by chest/abdomen/pelvis CT exam. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Infarct Scar Size (ISS) Over 18 Month Period | Change in infarct scar size (ISS) between baseline and 6-month and 18 month visits as determined by delayed contrast-enhanced MRI. | Baseline, 6 Months, 18 Months | 
| Left Ventricular Function (LVF) in Region of MSC Injection | The Left Ventricular Function differences in the region of MSC injection were evaluated. LVF is evaluated via ECHO as the percentage of ejected blood. | Assessed at Baseline and 18 Months | 
| Regional Left Ventricular Wall Thickening | Difference between baseline and 18 month regional left ventricular wall thickening as determined by MRI. | Assessed at Baseline and 18 months | 
| Left Ventricular End Diastolic Wall Thickness | Difference between the baseline and 18 month left ventricular end diastolic wall thickness as determined by MRI and echocardiogram. | Assessed at Baseline and 18 months | 
| Change in Left Ventricular End Diastolic and Systolic Volume | Change in left ventricular end diastolic and systolic volume as determined by MRI and echocardiogram. | Baseline, 6 Months, 18 Months | 
| Change in Left Ventricular Ejection Fraction | Change between baseline to 6-month and 18-month left ventricular ejection fraction (LVEF) as determined by MRI and echocardiogram. | Baseline to 6 Months, Baseline to 18 Months | 
| Change in Peak Volume Oxygen | Change in Peak VO2 as determined by treadmill test (mL/mg/min) from Baseline to 6 and from baseline to 18 months | Baseline, 6 Months, 18 Months | 
| Change in Six Minute Walk Test | Change in Six Minute Walk Test (in meters) from Baseline to 6 Months and Baseline to 18 Months | Baseline, 6 Months, 18 Months | 
| Change in NYHA Functional Class | Change in New York Heart Association (NYHA) Functional Classification based on patient's self reported activity level. Worsened: documented increase in limitations of physical activity as self-described by subject Improved: documented decrease in limitations of physical activity as self-described by subject Unchanged: no documented change in limitations of physical activity as self-described by subject | Baseline to 6 Months, 6 months to 18 Months | 
| Minnesota Living With Heart Failure Questionnaire Scores | Minnesota Living with Heart Failure (MLHF) questionnaire has a total score from 0 to 105. A higher score indicates that participants heart failure is preventing them from living their lives measured at two time points. | Assessed at 6 Months and 18 Months | 
| Incidence of Major Adverse Cardiac Events (MACE) | Incidence of Major Adverse Cardiac Events (MACE). A composite incidence of (1) death, (2) hospitalization for heart failure, or (3) non-fatal recurrent Ml. | 18 Months | 
| Number of Participants With Abnormal 48-Hour Ambulatory ECG Recordings | Ambulatory ECG monitoring is the most widely employed technology for the evaluation of a patient with symptoms suggestive of cardiac arrhythmia or conduction abnormality. When the patient returns for follow up the 48- Hour Ambulatory monitor provides the data to the site staff to detect any abnormal recordings based upon standard ECG protocol. | Assessed at 6 Months, 12 Months, and 18 Months | 
| Change in Pulmonary Function | Change in Pulmonary Function from Baseline to 6 month, Baseline to 12 month, and Baseline to 18 month visits as measured by forced expiratory volume in 1 second (FEV1) | Baseline, 6 Months, 12 Months, 18 Months | 
| Serial Troponin Values (ng/mL) | Serial Troponin Values (ng/mL) Values from Baseline to 48 Hours Post CABG | Assessed at Baseline, 12 hours, 24 hours, 36 hours, and 48 hours post CABG | 
| Creatinine Kinase - Muscle/Brain (MB) (ng/mL) | Creatinine Kinase MB (ng/mL) Values every 12 hours from Baseline to 48 Hours Post CABG | Assessed at Baseline, 12 Hours, 24 Hours, 36 Hours, and 48 hours post CABG | 
| Number of Clinically Significant Laboratory Values | Clinically significant laboratory values are first determined via standard laboratory normal values from a CAP and CLIA certified Laboratory and then assessed by investigator based on specific patient conditions and disease state. | 18 Months | 
| Rate of Treatment Emergent Adverse Events | Rate of Treatment Emergent Adverse Events Post Coronary Artery Bypass Graft (CABG) at 6 Months, 12 Months, and 18 Months | Assessed at 6 Months, 12 Months, and 18 Months | 
| Number of Abnormal Echocardiogram Readings 2 Days Post CABG. | The number of abnormal Echocardiogram readings 2 Days Post CABG will be documented based on transthoracic Echocardiographic standards. However, although Echocardiograms 2 days post CABG operation may show abnormalities which is standard in this population, this testing is instrumental because it measures End- diastolic wall thickness and Left ventricular volumes at end-diastole and end-systole. | Day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Ischemic Left Ventricular Dysfunction