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 cMRIChange 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 cMRIChange 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
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