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

A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, & Efficacy of Autologous Mesenchymal Stem Cells & C-kit+ Cardiac Stem Cells, Alone or in Combination, Administered Transendocardially in Subjects With Ischemic HF

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+ cells 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.

This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and c-kit+ cells 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, c-kit+ cells, or placebo. After randomization, baseline imaging, relevant 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 receive study product injection (cells or placebo) 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, however an as treated analysis will also be conducted.

Inclusion Criteria:

1. Be ≥ 21 and <80 years of age
2. Have documented coronary artery disease (CAD) with evidence of myocardial injury, LV dysfunction, and clinical evidence of HF
3. Have a "detectable" area of myocardial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement by cMRI
4. Have an EF ≤ 40% by cMRI
5. Be receiving guideline-driven medical therapy for heart failure at stable and tolerated doses for ≥ 1 month prior to consent. For beta-blockade "stable" is defined as no greater than a 50% reduction in dose or no more than a 100% increase in dose.
6. Be a candidate for cardiac catheterization
7. Have NYHA class I, 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 imminent 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. Indication for imminent heart transplantation is defined as a high likelihood of transplant prior to collection of the 12 month study endpoint. Candidates cannot be UNOS status 1A or 1B, and they must have documented low probability of being transplanted

2. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe (any valve) insufficiency/regurgitation within 12 months of consent

3. Aortic stenosis with valve area ≤ 1.5 cm2

4. History of ischemic or hemorrhagic stroke within 90 days of consent

5. History of a left ventricular remodeling surgical procedure utilizing prosthetic material

6. 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, or abandoned leads
   • subcutaneous ICDs
   • leadless pacemakers
   • any other condition that, in the judgment of device-trained staff, would deem an MRI contraindicated

7. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded)

8. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent

9. Other MRI contraindications (e.g. patient body habitus incompatible with MRI)

10. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent

11. 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

12. Presence of LV thrombus

13. Evidence of active myocarditis

14. Baseline maximal oxygen consumption (VO2 max) greater than 75% of age and gender based predictive values

15. Baseline eGFR <35 ml/min/1.73m2

16. Blood glucose levels (HbA1c) >10%

17. Hematologic abnormality evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet count < 100,000/ul

18. Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the upper limit of normal (ULN)

19. 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.

20. HIV and/or active hepatitis B virus (HBV) or hepatitis C virus (HCV)

21. Allergy to radiographic contrast material that cannot adequately be managed by premedication

22. Known history of anaphylactic reaction to penicillin or streptomycin

23. Received gene or cell-based therapy from any source within the previous 12 months

24. History of malignancy within 5 years (i.e., subjects with prior malignancy must be disease free for 5 years), excluding basal cell carcinoma and cervical carcinoma in situ which have been definitively treated

25. Condition that limits lifespan to < 1 year

26. 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

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