Clinical trial NCT06145035: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Ischemic Heart Disease
Keywords: ischemic cardiopathy
UC-MSCs
Lead sponsor: University of Louisville
Sponsor class: OTHER
Collaborators: name: University of Miami
name: University of Texas
name: United States Department of Defense
First posted: 2023-11-22
Enrollment: 60
Sex: ALL
Minimum age (years): 21
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized, double blind, placebo controlled,
Primary purpose: TREATMENT

Brief summary: 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), 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), 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 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 followed by three doses of placebo. Patients in the repeated dose group will receive four doses of UC MSCs. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: change in LVEF (D LVEF) between baseline (M0) and 12 months after the first study product infusion (SPI) (M12)
timeFrame: Baseline, 12 months
Secondary outcomes:
measure: Change in LV end-systolic volume index (ESVI)
timeFrame: Baseline, 12 months
measure: Change in LV end-diastolic volume index (EDVI)
timeFrame: Baseline, 12 months
measure: Change in LV end-diastolic wall thickness
timeFrame: Baseline, 12 months
measure: Change in LV wall thickening
timeFrame: Baseline, 12 months
measure: Change in LV sphericity index
timeFrame: Baseline, 12 months
measure: Change in global and regional strain (tagged MRI): global and 16-segment values for peak circumferential strain, global and segmental longitudinal strain
timeFrame: Baseline, 12 months
measure: Change in scar mass (in grams)
timeFrame: Baseline, 12 months
measure: Change in scar mass (as %LV)
timeFrame: Baseline, 12 months
measure: Change in VO2 max (treadmill test)
timeFrame: Baseline, month 8, month 12
measure: Change in exercise tolerance (six-minute walk test)
timeFrame: Baseline, month 8, month 12
measure: Change in New York Heart Association class
timeFrame: Baseline, month 2,4,6,8, & 12
measure: Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score
timeFrame: Baseline, month 6, month 12
measure: Change in Endothelial Progenitor Cell [EPC]-colony forming unit [EPC-CFU] assay
timeFrame: Baseline, month 2, 8, & 12
measure: Change in branchial artery flow-mediated dilation [FMD] [diameter percent change]).
timeFrame: Baseline, month 2, 8, & 12
measure: Major adverse cardiac events (MACE)
timeFrame: Month 12
measure: Cumulative days alive and out of hospital for HF
timeFrame: Month 12
measure: Biomarkers: Change in NT-proBNP
timeFrame: Day 0, Month 2, 4, 6, 8, & 12
measure: Biomarkers: hs-CRP
timeFrame: Day 0, Week 1, Month 2, 4, 6, 8, & 12
Other outcomes:
measure: Serious adverse events
timeFrame: 2 hrs, 6 hrs, Months 2 & 6
Locations:
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Louisville
country: United States
facility: University of Louisville School of Medicine, Institute of Molecular Cardiology
state: Kentucky
city: Houston
country: United States
facility: The Texas Heart Institute Houston Texas
state: Texas
Study officials:
affiliation: University of Louisville School of Medicine
name: Roberto Bolli, MD
role: PRINCIPAL_INVESTIGATOR
References: