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CLINICAL RESEARCH: CLINICAL TRIAL

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction

Joshua M. Hare, MD^_*,_*, Jay H. Traverse, MD, Timothy D. Henry, MD, Nabil Dib, MD, Robert K. Strumpf, MD, Steven P. Schulman, MD, Gary Gerstenblith, MD, Anthony N. DeMaria, MD^||, Ali E. Denktas, MD^¶, Roger S. Gammon, MD^#, James B. Hermiller, Jr, MD^_**, Mark A. Reisman, MD, Gary L. Schaer, MD and Warren Sherman, MD

^_* Department of Medicine, Cardiovascular Division and the Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida
Minneapolis Heart Institute, Minneapolis, Minnesota
Arizona Heart Institute, Phoenix, Arizona
The Johns Hopkins Hospital, Baltimore, Maryland
^|| University of California San Diego, San Diego, California
^¶ University of Texas Houston Medical School, Houston, Texas
^# Heart Hospital of Austin, Austin, Texas
^_** The Care Group, LLC, Indianapolis, Indiana
Swedish Medical Center, Seattle, Washington
Rush University Medical Center, Chicago, Illinois
New York Presbyterian Hospital, New York, New York

Manuscript received March 17, 2009; revised manuscript received May 20, 2009, accepted June 15, 2009.

^_* Reprint requests and correspondence: Dr. Joshua M. Hare, Leonard M. Miller School of Medicine, Interdisciplinary Stem Cell Institute and Division of Cardiology, Biomedical Research Building, Room 824, P.O. Box 016960 (R-125), Miami, Florida 33136 (Email: jhare{at}med.miami.edu).

Objectives: Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI).

Background: Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support.

Methods: We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points.

Results: Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p = 0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p = 0.003) in the hMSC-treated patients. Global symptom score in all patients (p = 0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling.

Conclusions: Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452)

Key Words: magnetic resonance imaging • echocardiography • allogeneic • mesenchymal stem cells

Abbreviations and Acronyms   AE = adverse event   BMC = bone marrow mononuclear cell   FEV1 = forced expiratory volume in 1 s   hMSC = human mesenchymal stem cell   LVEF = left ventricular ejection fraction   MI = myocardial infarction   MRI = magnetic resonance imaging   PVC = premature ventricular contraction   VT = ventricular tachycardia

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