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

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ClinicalTrials.gov Identifier: NCT00587990
Recruitment Status : Terminated (Difficulty in recruitment.)
First Posted : January 8, 2008
Results First Posted : April 2, 2015
Last Update Posted : September 10, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University Specialized Center for Cell Based Therapy
The Emmes Company, LLC
Information provided by (Responsible Party):
Joshua M Hare, University of Miami

Tracking Information
First Submitted Date  ICMJE January 2, 2008
First Posted Date  ICMJE January 8, 2008
Results First Submitted Date  ICMJE January 30, 2015
Results First Posted Date  ICMJE April 2, 2015
Last Update Posted Date September 10, 2019
Study Start Date  ICMJE November 2007
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 19, 2019)
Number of Patients With Serious Adverse Events [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00587990 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 19, 2019)
  • Change in Infarct Scar Size (ISS) Over 18 Month Period [ Time Frame: 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 Function (LVF) in Region of MSC Injection [ Time Frame: 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.
  • Regional Left Ventricular Wall Thickening [ Time Frame: Assessed at Baseline and 18 months ]
    Difference between baseline and 18 month regional left ventricular wall thickening as determined by MRI.
  • Left Ventricular End Diastolic Wall Thickness [ Time Frame: 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 End Diastolic and Systolic Volume [ Time Frame: Baseline, 6 Months, 18 Months ]
    Change in left ventricular end diastolic and systolic volume as determined by MRI and echocardiogram.
  • Change in Left Ventricular Ejection Fraction [ Time Frame: 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.
  • Change in Peak Volume Oxygen [ Time Frame: 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 Six Minute Walk Test [ Time Frame: Baseline, 6 Months, 18 Months ]
    Change in Six Minute Walk Test (in meters) from Baseline to 6 Months and Baseline to 18 Months
  • Change in NYHA Functional Class [ Time Frame: 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
  • Minnesota Living With Heart Failure Questionnaire Scores [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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.
  • Change in Pulmonary Function [ Time Frame: 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)
  • Serial Troponin Values (ng/mL) [ Time Frame: 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) [ Time Frame: 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
  • Number of Clinically Significant Laboratory Values [ Time Frame: 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.
  • Rate of Treatment Emergent Adverse Events [ Time Frame: 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 Abnormal Echocardiogram Readings 2 Days Post CABG. [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS)
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Stem Cell Transplantation
  • Ventricular Dysfunction, Left
Intervention  ICMJE
  • Biological: Lower dose mesenchymal stem cell (MSC) injection
    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.
  • Genetic: Placebo
    Participants will receive between 10 and 20 placebo injections that consist of phosphate buffered saline (PBS) and 1% human serum albumin (HSA).
  • Biological: Higher dose MSC injection
    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.
Study Arms  ICMJE
  • Experimental: 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
    Intervention: Biological: Lower dose mesenchymal stem cell (MSC) injection
  • Experimental: Higher dose MSC injection
    Participants will receive higher dose of mesenchymal stem cell injections for a total of 2 x 10^8 cells
    Intervention: Biological: Higher dose MSC injection
  • Placebo Comparator: (3) Placebo
    Participants will receive placebo injections
    Intervention: Genetic: Placebo
Publications * Karantalis V, DiFede DL, Gerstenblith G, Pham S, Symes J, Zambrano JP, Fishman J, Pattany P, McNiece I, Conte J, Schulman S, Wu K, Shah A, Breton E, Davis-Sproul J, Schwarz R, Feigenbaum G, Mushtaq M, Suncion VY, Lardo AC, Borrello I, Mendizabal A, Karas TZ, Byrnes J, Lowery M, Heldman AW, Hare JM. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ Res. 2014 Apr 11;114(8):1302-10. doi: 10.1161/CIRCRESAHA.114.303180. Epub 2014 Feb 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 1, 2015)
9
Original Estimated Enrollment  ICMJE
 (submitted: January 3, 2008)
45
Actual Study Completion Date  ICMJE June 2011
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00587990
Other Study ID Numbers  ICMJE 20070598
U54HL081028 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Joshua M Hare, University of Miami
Study Sponsor  ICMJE Joshua M Hare
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Johns Hopkins University Specialized Center for Cell Based Therapy
  • The Emmes Company, LLC
Investigators  ICMJE
Principal Investigator: Joshua M. Hare, MD University of Miami
Principal Investigator: Gary Gerstenblith, MD Johns Hopkins University
Principal Investigator: John V. Conte, MD Johns Hopkins University
Principal Investigator: Steven P. Schulman, MD Johns Hopkins University
PRS Account University of Miami
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP