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

Official title

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

Overview

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).

Detailed description

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.

Interventions

• Biological umbilical cord-derived mesenchymal stromal cells (UC-MSCs)
  The study product will consist of 100 million UC-MSCs suspended in a final volume of 60 ml given at a rate of 3.3 million cells/min. The product will be infused into vein via intravenous line placed in the arm.

Primary outcome measures

• change in LVEF (D LVEF) between baseline (M0) and 12 months after the first study product infusion (SPI) (M12) [Time frame: Baseline, 12 months]

Secondary outcome measures (12)

• Change in LV end-systolic volume index (ESVI) [Time frame: Baseline, 12 months]
• Change in LV end-diastolic volume index (EDVI) [Time frame: Baseline, 12 months]
• Change in LV end-diastolic wall thickness [Time frame: Baseline, 12 months]
• Change in LV wall thickening [Time frame: Baseline, 12 months]
• Change in LV sphericity index [Time frame: Baseline, 12 months]
• Change in global and regional strain (tagged MRI): global and 16-segment values for peak circumferential strain, global and segmental longitudinal strain [Time frame: Baseline, 12 months]
• Change in scar mass (in grams) [Time frame: Baseline, 12 months]
• Change in scar mass (as %LV) [Time frame: Baseline, 12 months]
• Change in VO2 max (treadmill test) [Time frame: Baseline, month 8, month 12]
• Change in exercise tolerance (six-minute walk test) [Time frame: Baseline, month 8, month 12]
• Change in New York Heart Association class [Time frame: Baseline, month 2,4,6,8, & 12]
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score [Time frame: Baseline, month 6, month 12]

Eligibility criteria

Inclusion criteria

• Be ≥ 21 and ≤ 85 years of age.
• Have documented CAD (> 70% lesion in at least 1 epicardial vessel) with evidence of myocardial injury, LV dysfunction, and clinical evidence of HF.
• Have a "detectable" area of myocardial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement by MRI.
• Have an EF ≤ 40% by MRI.
• 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.
• Have NYHA class I, II or III symptoms of HF (see Appendix A)
• 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

• 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.
• Severe valvular (any valve) insufficiency and/or regurgitation within 12 months of consent
• History of ischemic or hemorrhagic stroke within 90 days of consent
• 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
• Pacemaker dependence with an ICD (Note: pacemaker dependent candidates without an ICD are not excluded)
• A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent.
• Other MRI contraindications (e.g. patient body habitus incompatible with MRI)
• An appropriate ICD firing or anti tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent
• 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
• Evidence of active myocarditis
• Baseline glomerular filtration rate (eGFR) < 35 ml/min/1.73m2
• Blood glucose levels (HbA1c) >10%
• Hematologic abnormality evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet count < 100,000/ul
• Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the ULN.
• HIV and/or active HBV or HCV
• Known history of anaphylactic reaction to penicillin or streptomycin
• Received gene or cell based therapy from any source within the previous 12 months.
• 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.
• Condition that limits lifespan to < 1 year
• 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.
• Participation in an investigational therapeutic or device trial within 30 days of consent
• Cognitive or language barriers that prohibit obtaining informed consent or any study elements
• Pregnancy or lactation or plans to become pregnant in the next 12 months.
• Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow up.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 3 centers

• University of Miami Miller School of Medicine — Miami
• University of Louisville School of Medicine, Institute of Molecular Cardiology — Louisville
• The Texas Heart Institute Houston Texas — Houston

Publications

• Bolli R, Tang XL, Hare JM, Mitrani RD, Perin EC, Lima JA, Hurwitz BE, Kalra D, Singh G, Saltzman RG, Caceres LV, Nettina A, Lee YS, Bacallao K, Grant E, Khan A. Design and rationale of CATO, a Phase IIA, randomized, double-blind, placebo-controlled study of single or repeated intravenous administration of umbilical cord-derived mesenchymal stromal cells in ischemic cardiomyopathy. Am Heart J. 2026 PMID 41397478
• Tang XL, Wysoczynski M, Gumpert AM, Solanki M, Li Y, Wu WJ, Zheng S, Ruble H, Li H, Stowers H, Zheng S, Ou Q, Tanveer N, Slezak J, Kalra DK, Bolli R. Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischaemic cardiomyopathy. Cardiovasc Res. 2024 Dec 4;120(15):1939-1952. doi: 10.1093/cvr/cvae173. PMID 39163570

Identifiers

NCT: NCT06145035 · 23.0712 · 1369707

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗