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

Phase 1

Terminated

Conditions: Stem Cell Transplantation
Ventricular Dysfunction, Left

Interventions: Biological: Higher dose MSC injection
Genetic: Placebo
Biological: Lower dose mesenchymal stem cell (MSC) injection

Registration Number: NCT00587990

Lead Sponsor: Joshua M Hare

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Higher dose MSC injection	Higher dose MSC injection	Participants will receive higher dose of mesenchymal stem cell injections for a total of 2 x 10\^8 cells
(3) Placebo	Placebo	Participants will receive placebo injections
Lower dose mesenchymal stem cell (MSC) injection	Lower dose mesenchymal stem cell (MSC) injection	Participants will receive lower dose mesenchymal stem cell injections for a total of 2 x 10\^7 cells

Primary Outcome Measures

Name	Time	Method
Number of Patients With Serious Adverse Events	12 Months	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.

Secondary Outcome Measures

Name	Time	Method
Left Ventricular Function (LVF) in Region of MSC Injection	Assessed at Baseline and 18 Months	The Left Ventricular Function differences in the region of MSC injection were evaluated. LVF is evaluated via ECHO as the percentage of ejected blood.
Change in Peak Volume Oxygen	Baseline, 6 Months, 18 Months	Change in Peak VO2 as determined by treadmill test (mL/mg/min) from Baseline to 6 and from baseline to 18 months
Change in NYHA Functional Class	Baseline to 6 Months, 6 months to 18 Months	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
Change in Left Ventricular End Diastolic and Systolic Volume	Baseline, 6 Months, 18 Months	Change in left ventricular end diastolic and systolic volume as determined by MRI and echocardiogram.
Change in Six Minute Walk Test	Baseline, 6 Months, 18 Months	Change in Six Minute Walk Test (in meters) from Baseline to 6 Months and Baseline to 18 Months
Minnesota Living With Heart Failure Questionnaire Scores	Assessed at 6 Months and 18 Months	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.
Incidence of Major Adverse Cardiac Events (MACE)	18 Months	Incidence of Major Adverse Cardiac Events (MACE). A composite incidence of (1) death, (2) hospitalization for heart failure, or (3) non-fatal recurrent Ml.
Number of Participants With Abnormal 48-Hour Ambulatory ECG Recordings	Assessed at 6 Months, 12 Months, and 18 Months	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.
Regional Left Ventricular Wall Thickening	Assessed at Baseline and 18 months	Difference between baseline and 18 month regional left ventricular wall thickening as determined by MRI.
Change in Pulmonary Function	Baseline, 6 Months, 12 Months, 18 Months	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)
Change in Infarct Scar Size (ISS) Over 18 Month Period	Baseline, 6 Months, 18 Months	Change in infarct scar size (ISS) between baseline and 6-month and 18 month visits as determined by delayed contrast-enhanced MRI.
Left Ventricular End Diastolic Wall Thickness	Assessed at Baseline and 18 months	Difference between the baseline and 18 month left ventricular end diastolic wall thickness as determined by MRI and echocardiogram.
Change in Left Ventricular Ejection Fraction	Baseline to 6 Months, Baseline to 18 Months	Change between baseline to 6-month and 18-month left ventricular ejection fraction (LVEF) as determined by MRI and echocardiogram.
Serial Troponin Values (ng/mL)	Assessed at Baseline, 12 hours, 24 hours, 36 hours, and 48 hours post CABG	Serial Troponin Values (ng/mL) Values from Baseline to 48 Hours Post CABG
Creatinine Kinase - Muscle/Brain (MB) (ng/mL)	Assessed at Baseline, 12 Hours, 24 Hours, 36 Hours, and 48 hours post CABG	Creatinine Kinase MB (ng/mL) Values every 12 hours from Baseline to 48 Hours Post CABG
Rate of Treatment Emergent Adverse Events	Assessed at 6 Months, 12 Months, and 18 Months	Rate of Treatment Emergent Adverse Events Post Coronary Artery Bypass Graft (CABG) at 6 Months, 12 Months, and 18 Months
Number of Clinically Significant Laboratory Values	18 Months	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.
Number of Abnormal Echocardiogram Readings 2 Days Post CABG.	Day 2	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.

Trial Locations

Locations (2): University of Miami Miller School of Medicine
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Miami, Florida, United States
Johns Hopkins University School of Medicine
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Baltimore, Maryland, United States