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Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure

Information source: The University of Texas Health Science Center, Houston
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Ischemic Cardiomyopathy

Intervention: Mesenchymal Stem Cells (MSC) (Biological); Cardiac Stem Cells (CSC) (Biological); Placebo (Plasmalyte A) (Biological)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: The University of Texas Health Science Center, Houston

Official(s) and/or principal investigator(s):
Robert Simari, MD, Study Chair, Affiliation: CCTRN Steering Committee Chair

Overall contact:
Rachel Vojvodic, MPH, Phone: 713-500-9528, Email: Rachel.W.Vojvodic@uth.tmc.edu

Summary

This is a phase II, randomized, placebo-controlled clinical trial designed to assess feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) both alone and in combination (Combo), compared to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by transendocardial injection in subjects with ischemic cardiomyopathy.

Clinical Details

Official title: A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, and Efficacy of Autologous Mesenchymal Stem Cells and C-kit+ Cardiac Stem Cells, Alone or in Combination, Administered Transendocardially in Subjects With Ischemic Heart Failure

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Change in Left Ventricular Ejection Fraction (LVEF) as measured by cMRI

Change in Global Strain (HARP MRI) as measured by cMRI

Change in Regional Strain (HARP MRI) as measured by cMRI

Change in Left Ventricular End Diastolic Volume Index (LVEDVI) as measured by cMRI

Change in Left Ventricular End Systolic Volume Index (LVESVI) as measured by cMRI

Change in Left Ventricular Sphericity Index as measured by cMRI

Change in Infarct/scar Volume (DEMRI) as measured by cMRI

Change in Maximal Oxygen Consumption (VO2 max) as measured by treadmill

Change in Exercise Tolerance as measured by the six minute walk test

Change in Minnesota Living with Heart Failure Questionnaire (MHLFQ) Score

Incidence rate of Major Adverse Cardiac Events (MACE)

Cumulative Days alive and out of hospital

Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured by blood draw

Secondary outcome:

Change in Left Ventricular Ejection Fraction (LVEF) as measured by cMRI

Change in Global Strain (HARP MRI) as measured by cMRI

Change in Regional Strain (HARP MRI) as measured by cMRI

Change in Left Ventricular End Diastolic Volume Index (LVEDVI) as measured by cMRI

Change in Left Ventricular End Systolic Volume Index (LVESVI) as measured by cMRI

Change in Left Ventricular Sphericity Index as measured by cMRI

Change in Infarct/scar Volume (DEMRI) as measured by cMRI

Change in Maximal Oxygen Consumption (VO2 max) as measured by treadmill

Change in Exercise Tolerance as measured by the six minute walk test

Change in Minnesota Living with Heart Failure Questionnaire (MHLFQ) Score

Incidence rate of Major Adverse Cardiac Events (MACE)

Cumulative Days alive and out of hospital

Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured by blood draw

Detailed description: This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and CSCs alone compared with placebo as well as each other in subjects with heart failure of ischemic etiology. Following a successful lead-in phase, a total of one hundred forty-four (144) subjects will be randomized (1: 1:1: 1) to receive Combo, MSCs, CSCs, or placebo. After randomization, baseline imaging, harvest procedures, and study product injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post study product injection. All subjects will undergo bone marrow aspiration, endomyocardial biopsy, cardiac catheterization, and study product injection using the NOGA® XP Mapping and Navigation System. Subjects will have delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and LV function and structure at baseline and at 6 and 12 months post study product administration. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 ±30 days and 365 ±30 days respectively from the day of study product injection (Day 0). For the purpose of the endpoint analysis and safety evaluations, the Investigators will utilize an "intention-to-treat" study population.

Eligibility

Minimum age: 21 Years. Maximum age: 79 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Be ≥ 21 and <80 years of age 2. Have a diagnosis of chronic ischemic left ventricular dysfunction secondary to myocardial infarction (MI) defined by clinical criteria 3. Have a "sizable" area of myocardial injury defined as ≥ 10% LV involvement (infarct volume) and any subendocardial involvement by cardiac magnetic resonance imaging (cMRI) 4. Have an EF ≤ 40% by cMRI 5. Be receiving appropriate doses of "maximal medical therapy" for heart failure, or post-infarction left ventricular dysfunction for ≥ 1 month prior to consent. That is, beta-blockade must be prescribed at a stable dose ("stable" defined as no greater than a 50% reduction in dose or no more than a 100% increase in dose). Angiotensin-converting enzyme (ACE) inhibition (or angiotensin-receptor blockade if ACE inhibition intolerant) must be prescribed at a stable dose. Additionally, aldosterone blockade must be prescribed at a stable dose unless contraindicated (e. g., hyperkalemia). 6. Be a candidate for cardiac catheterization 7. Have New York Heart Association (NYHA) class II or III heart failure symptoms 8. If a female of childbearing potential, be willing to use one form of birth control for the duration of the study, and undergo a pregnancy test at baseline and within 36 hours prior to injection Exclusion Criteria: 1. Indication for standard-of-care surgery (including valve surgery, placement of left-ventricular assist device, or heart transplantation), coronary artery bypass grafting (CABG) procedure, and/or percutaneous coronary intervention (PCI) for the treatment of ischemic and/or valvular heart disease. Subjects who require or undergo PCI should undergo these procedures a minimum of 3 months in advance of randomization. Subjects who require or undergo CABG should undergo these procedures a minimum of 4 months in advance of randomization. In addition, subjects who develop a need for revascularization following enrollment should undergo revascularization without delay. 2. Severe valvular heart disease including mechanical or bioprosthetic heart valve or moderate to severe aortic insufficiency (ventriculogram or echocardiographic assessment of aortic insufficiency graded as > +2 within 12 months of consent) 3. Aortic stenosis with valve area ≤ 1. 5 cm2 4. History of a left ventricular remodeling surgical procedure utilizing prosthetic material 5. Presence of a pacemaker and/or implantable cardioverter-defibrillator (ICD) generator with any of the following limitations/conditions:

- manufactured before the year 2000

- leads implanted < 6 weeks prior to consent

- non-transvenous epicardial, abandoned, or no-fixation leads

- subcutaneous ICDs

- leadless pacemakers

- any other condition that, in the judgment of device-trained staff, would deem an

MRI contraindicated 6. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded) 7. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent 8. Other MRI contraindications (e. g. patient body habitus incompatible with MRI) 9. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent 10. Ventricular tachycardia ≥ 20 consecutive beats without an ICD within 3 months of consent, or symptomatic Mobitz II or higher degree atrioventricular block without a functioning pacemaker within 3 months of consent 11. Presence of LV thrombus 12. Baseline maximal oxygen consumption (VO2 max) greater than two standard deviations below normal age and gender based ml/kilo/minute 13. Ability to walk ≥ age and gender specified criteria on the baseline six minute walk tests 14. Baseline glomerular filtration rate (eGFR) < 40 ml/min/1. 73m2 estimated using MDRD 15. Poorly controlled blood glucose levels (HbA1c > 8. 5%) and/or history of proliferative retinopathy 16. Hematologic abnormality evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet count < 100,000/ul 17. Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the upper limit of normal (ULN) 18. Coagulopathy (INR ≥ 1. 3) not due to a reversible cause (e. g., warfarin and/or Factor Xa inhibitors). Subjects who cannot be withdrawn from anticoagulation will be excluded. 19. HIV and/or active hepatitis B virus (HBV) or hepatitis C virus (HCV) 20. Allergy to radiographic contrast material that cannot adequately be managed by premedication 21. Known allergies to penicillin or streptomycin 22. History of organ or cell transplantation, except for bone, skin, ligament, tendon, or cornea grafting 23. History of malignancy within 5 years (i. e., subjects with prior malignancy must be disease free for 5 years), excluding basal cell carcinoma with clean border pathology report and cervical carcinoma in situ which have been definitively treated 24. Condition that limits lifespan to < 1 year 25. History of drug abuse (illegal "street" drugs except marijuana, or prescription medications not being used appropriately for a pre-existing medical condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months 26. Chronic immunosuppressant therapy such as corticosteroids or tumor necrosis factor alpha (TNFα) antagonists 27. Participation in an investigational therapeutic or device trial within 30 days of consent 28. Cognitive or language barriers that prohibit obtaining informed consent or any study elements 29. Pregnancy or lactation or plans to become pregnant in the next 12 months 30. Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow-up

Locations and Contacts

Rachel Vojvodic, MPH, Phone: 713-500-9528, Email: Rachel.W.Vojvodic@uth.tmc.edu

Stanford University School of Medicine (Falk Cardiovascular Research Center), Stanford, California 94305, United States; Not yet recruiting
Fouzia Khan, Phone: 650-736-1410, Email: fouziak@stanford.edu
Phil Yang, MD, Principal Investigator

University of Florida-Department of Medicine, Gainesville, Florida 32610, United States; Not yet recruiting
Dana Leach, Phone: 352-273-8930, Email: Dana.Leach@medicine.ufl.edu
Sarah Long, Phone: 352-273-8932, Email: Sarah.Long@medicine.ufl.edu
Carl J Pepine, MD, Principal Investigator

University of Miami-Interdisciplinary Stem Cell Institute, Miami, Florida 33101, United States; Not yet recruiting
Darcy DiFede, Phone: 305-243-9106, Email: ddifede@med.miami.edu
Cindy Delgado, Email: cdelgado5@med.miami.edu
Joshua Hare, MD, Principal Investigator

Indiana Center for Vascular Biology and Medicine, Indianapolis, Indiana 46202, United States; Not yet recruiting
Toni Lathrop, Phone: 317-278-6107, Email: Lathrop@iu.edu
Adnan Malik, MD, Principal Investigator

University of Louisville, Louisville, Kentucky 40202, United States; Not yet recruiting
Anne Marie Webb, Phone: 502-587-4106, Email: anne.webb@louisville.edu
Roberto Bolli, MD, Principal Investigator

Minneapolis Heart Institute Foundation, Minneapolis, Minnesota 55407, United States; Not yet recruiting
Patricia Mitchell, Phone: 612-863-6287, Email: patricia.mitchell@allina.com
Jay Traverse, MD, Principal Investigator

Texas Heart Institute, Houston, Texas 77030, United States; Not yet recruiting
Kerry Blakeney, Phone: 832-355-9495, Email: kblakeney@texasheart.org
Nichole Piece, Phone: 832-355-9173, Email: npiece@texasheart.org
James T Willerson, MD, Principal Investigator

Additional Information

Cardiovascular Cell Therapy Research Network

National Heart, Lung, and Blood Institute

Information on stem cells from the National Institutes of Health

Related publications:

Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, March KL, Murphy MP, Pepine CJ, Simari RD, Skarlatos SI, Traverse JH, Willerson JT, Szady AD, Taylor DA, Vojvodic RW, Yang PC, Moyé LA; Cardiovascular Cell Therapy Research Network. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013 Apr 16;127(15):1630-5. doi: 10.1161/CIRCULATIONAHA.112.000779.

Nazarian S, Halperin HR. How to perform magnetic resonance imaging on patients with implantable cardiac arrhythmia devices. Heart Rhythm. 2009 Jan;6(1):138-43. doi: 10.1016/j.hrthm.2008.10.021. Epub 2008 Oct 22. Review.

Starting date: October 2015
Last updated: July 16, 2015

Page last updated: August 23, 2015

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