title: Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.
abstract: OBJECTIVE
  This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance.
  
  
  METHODS
  This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion.
  
  
  CONCLUSIONS
  This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).
authors.affiliation: aDivision of Cardiology, Duke University Medical Center, Durham, North Carolina bMedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, District of Columbia cDivision of Cardiology, Emory University, Atlanta, Georgia dDivision of Cardiology, Northwestern University Feinberg School of Medicine eDivision of Cardiology, Stony Brook University, Stony Brook, New York fCardioCell LLC gStemedica Cell Technologies Inc, San Diego, California hCenter for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kim
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.forename: Robert T
authors.initials: RT
authors.lastname: Cole
authors.forename: Allen S
authors.initials: AS
authors.lastname: Anderson
authors.forename: Jane E
authors.initials: JE
authors.lastname: Wilcox
authors.forename: Hal A
authors.initials: HA
authors.lastname: Skopicki
authors.forename: Sergey
authors.initials: S
authors.lastname: Sikora
authors.forename: Lev
authors.initials: L
authors.lastname: Verkh
authors.forename: Nikolai I
authors.initials: NI
authors.lastname: Tankovich
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
mesh_terms: D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery*; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004452:Echocardiography; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery*; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D009206:Myocardium / Q000473:pathology; D010865:Pilot Projects; D020127:Recovery of Function; D012107:Research Design; D016037:Single-Blind Method; D013318:Stroke Volume; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling