Single or Repeated Intravenous Administration of umbiliCAl Cord Mesenchymal sTrOmal Cells in Ischemic Cardiomyopathy

University of Louisville - 18642 / CATO Study, Single or Repeated Intravenous Administration of umbiliCAl Cord Mesenchymal sTrOmal Cells in Ischemic Cardiomyopathy

This is a Phase IIA, randomized, double blind, placebo controlled, multicenter study designed to assess the safety, feasibility, and efficacy of umbilical cord derived mesenchymal stromal cells (UC MSCs, stem cells), administered intravenously (IV) as a single dose or repeated doses, in patients with ischemic cardiomyopathy (ICM).

This is a Phase IIA, randomized, double blind, placebo controlled, multicenter study designed to assess the safety, feasibility, and efficacy of umbilical cord derived mesenchymal stromal cells (UC MSCs, stem cells), administered intravenously (IV) as a single dose or repeated doses, in patients with ischemic cardiomyopathy (ICM) (see summary in Figure 1).

A total of 60 participants will be assigned in a random fashion to three groups on a 1:1:1 basis: control, single dose, and repeated doses. All patients will receive four study product infusions (SPIs) 2 months apart. SPIs (performed in a double blind fashion) will consist of either UC MSCs (stem cells) or placebo (based on randomization), infused by the IV route. Patients in the control group will receive four doses of placebo. Patients in the single dose group will receive one dose of UC MSCs (stem cells) followed by three doses of placebo. Patients in the repeated dose group will receive four doses of UC MSCs (stem cells). A dose of UC MSCs will consist of 100 million cells suspended in 60 mL, infused at a rate of 2 mL/min. A dose of placebo will consist of an equivalent volume of Plasma Lyte A supplemented with 1% human serum albumin (HSA). After each SPI, patients will be monitored for a minimum of 2 hours and then examined at 1 week and 2 months. After the fourth SPI, patients will be followed for 6 months to complete all safety and efficacy assessments.

The UC MSCs will be derived from UC tissue obtained from a healthy pregnant woman at the time of caesarean delivery. The cells will be manufactured at the Interdisciplinary Stem Cell Institute at the University of Miami, Miller School of Medicine and then shipped to the Site for administration.

Inclusion Criteria:

1. Be ≥ 21 and ≤ 85 years of age.
2. Have documented CAD (> 70% lesion in at least 1 epicardial vessel) 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 MRI.
4. Have an EF ≤ 40% by MRI.
5. Be receiving guideline driven medical therapy for HF (beta blockers, diuretics, ACE inhibitors or ARBs, or ARNIs, aldosterone antagonists, hydralazine isosorbide, sodium-glucose transporter 2 inhibitors) ) at stable, maximally tolerated doses for ≥ 1 month prior to consent. "Stable" is defined as stable dose with no changes for 30 days after last dose adjustment. 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. Have NYHA class I, II or III symptoms of HF (see Appendix A)
7. If a female of childbearing potential, be willing to use one form of birth control for the duration of the study and undergo a serum pregnancy test at baseline and within 36 hours prior to infusion

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 3 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 1A or 1B, and they must have documented a low probability of being transplanted.

2. Severe valvular (any valve) insufficiency and/or regurgitation within 12 months of consent

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

4. Presence of a pacemaker and/or implantable cardiac device (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 (if not MRI compatible)
   • leadless pacemakers
   • any other condition that, in the judgment of device trained staff, would deem an MRI contraindicated

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

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

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

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

9. 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

10. Evidence of active myocarditis

11. Baseline glomerular filtration rate (eGFR) < 35 ml/min/1.73m2

12. Blood glucose levels (HbA1c) >10%

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

14. Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the ULN.

15. HIV and/or active HBV or HCV

16. Known history of anaphylactic reaction to penicillin or streptomycin

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

18. History of malignancy within 2 years (i.e., subjects with prior malignancy must be disease free for 2 years), excluding basal cell carcinoma and cervical carcinoma in situ which have been definitively treated.

19. Condition that limits lifespan to < 1 year

20. 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 12 months.

21. Participation in an investigational therapeutic or device trial within 30 days of consent

22. Cognitive or language barriers that prohibit obtaining informed consent or any study elements

23. Pregnancy or lactation or plans to become pregnant in the next 12 months.

24. Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow up.