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

• ClinicalTrials.gov Identifier: NCT06145035
• Recruitment Status: Recruiting
• First Posted: November 22, 2023
• Last Update Posted: March 7, 2024
• Sponsor: Roberto Bolli
• Collaborators: University of Miami; University of Texas; United States Department of Defense
• Information provided by (Responsible Party): Roberto Bolli, University of Louisville

Tracking Information

• First Submitted Date: November 1, 2023
• First Posted Date: November 22, 2023
• Last Update Posted Date: March 7, 2024
• Actual Study Start Date: March 4, 2024
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 17, 2023)

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

Change in left ventricular ejection fraction as assessed via cardiac MRI. Units: %

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 17, 2023)

• Change in LV end-systolic volume index (ESVI) [ Time Frame: Baseline, 12 months ]
  Change in left ventricular end systolic index (LVESVI) as assessed via cardiac MRI. Units: ml/m2
• Change in LV end-diastolic volume index (EDVI) [ Time Frame: Baseline, 12 months ]
  Change in left ventricular end diastolic index (LVEDVI) as assessed via cardiac MRI. Units: ml/m2
• Change in LV end-diastolic wall thickness [ Time Frame: Baseline, 12 months ]
  Change in LV end-diastolic wall thickness as assessed via cardiac MRI. Units: mm
• Change in LV wall thickening [ Time Frame: Baseline, 12 months ]
  Change in LV wall thickening as assessed via cardiac MRI. Units: mm
• Change in LV sphericity index [ Time Frame: Baseline, 12 months ]
  Change in LV sphericity index as assessed via cardiac MRI. Units: Index score Sphericity index is the ratio of the long and short axis measurements of the left ventricle.
• 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 global and regional strain as assessed via cardiac MRI. Units: %
• Change in scar mass (in grams) [ Time Frame: Baseline, 12 months ]
  Change in scar mass (in grams) as assessed via delayed gadolinium enhancement MRI. Units: grams
• Change in scar mass (as %LV) [ Time Frame: Baseline, 12 months ]
  Change in scar mass (as %LV) as assessed via delayed gadolinium enhancement MRI. Units: %
• Change in VO2 max (treadmill test) [ Time Frame: Baseline, month 8, month 12 ]
  Change in maximal oxygen consumption (peak VO2) as assessed via treadmill. Units: mL/kg/min
• Change in exercise tolerance (six-minute walk test) [ Time Frame: Baseline, month 8, month 12 ]
  Change in exercise tolerance as assessed as the distance covered via the six-minute walk test. Units: meters
• Change in New York Heart Association class [ Time Frame: Baseline, month 2,4,6,8, & 12 ]
  NYHA Classifications of heart failure are as follows: Class I (no limitations); Class II (mild symptoms); Class III (marked limitations); Class IV (Severe limitations). Units: score on a scale
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score [ Time Frame: Baseline, month 6, month 12 ]
  KCCQ is a 12-item questionnaire in which scores are scaled from 0 to 100 and summarized in ranges to represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent. Units: score on a scale
• Change in Endothelial Progenitor Cell [EPC]-colony forming unit [EPC-CFU] assay [ Time Frame: Baseline, month 2, 8, & 12 ]
  Change in endothelial function will be reported as the change in Endothelial Progenitor Cell Colony Forming Unit (EPC-CFU) assessed via blood sample assay. Units: CFUs/well
• Change in branchial artery flow-mediated dilation [FMD] [diameter percent change]). [ Time Frame: Baseline, month 2, 8, & 12 ]
  Change in branchial artery flow-mediated dilation will be reported as the percent change in flow mediated diameter assessed via flow mediated dilation (FMD). Units: %
• Major adverse cardiac events (MACE) [ Time Frame: Month 12 ]
  Number of participants with adjudicated events including death, hospitalization for worsening HF, and exacerbation of HF requiring visit to the Emergency Department and/or IV therapy but not requiring hospitalization. Units: number of participants who have an incidence of MACE in each group
• Cumulative days alive and out of hospital for HF [ Time Frame: Month 12 ]
  Days alive and out of hospital during the study evaluation period. Units: days
• Biomarkers: Change in NT-proBNP [ Time Frame: Day 0, Month 2, 4, 6, 8, & 12 ]
  Change in NT-proBNP as assessed via blood draw. Units: pg/ml
• Biomarkers: hs-CRP [ Time Frame: Day 0, Week 1, Month 2, 4, 6, 8, & 12 ]
  Blood level of hs-CRP as assessed via blood draw. Units: mg/ml
• Biomarkers: TNF-alpha, TNF-beta, IFN-gamma, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-18, TGFbeta, GM-CSF, VEGF [ Time Frame: Day 0, Week 1, Month 2, 4, 6, 8, & 12 ]
  Blood levels of TNF-alpha, TNF-beta, IFN-gamma, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-18, TGFbeta, GM-CSF, VEGF as assessed via blood draw. Units: pg/ml
• Biomarkers: NK cells, T cells (Tc, Th1, Th2, Th17, Treg), B cells, monocytes, Exhausted B cells and terminally differentiated effector memory CD45RA (TEMRA) T cells [ Time Frame: Day 0, Week 1, Month 2, 4, 6, 8, & 12 ]
  Blood levels of NK cells, T cells (Tc, Th1, Th2, Th17, Treg), B cells, monocytes, Exhausted B cells and terminally differentiated effector memory CD45RA (TEMRA) T cells. Units: cell/ul
• Biomarkers: Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios [ Time Frame: Day 0, Week 1, Month 2, 4, 6, 8, & 12 ]
  Blood levels of Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. Units: ratio

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: November 17, 2023)

Serious adverse events [ Time Frame: 2 hrs, 6 hrs, Months 2 & 6 ]

Number of patients experiencing significant adjudicated clinical events including myocardial infarction (MI), stroke, pulmonary embolism, implantable cardioverter-defibrillator (ICD) firing for ventricular fibrillation/tachycardia, ventricular tachycardia (sustained and non-sustained), or hospitalization related to intravenous infusion of UC-MSCs. Units: number of participants who have an incidence of SAE in each group

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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
• 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 1 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 4 hours ± 30 minutes 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

randomized, double blind, placebo controlled,

Masking: Double (Participant, Investigator)
Masking Description:

As a double-blind study, bias control will be achieved by maintaining the blind on treatment group assignments. The master randomization lists containing the treatment assignments will be protected in secure, controlled access drives/folders and will not be released to any blinded study personnel prior to final database lock. A centralized Core laboratory will be used for MRI analyses to maintain the blind across the study team.

The designated cell processing technicians will prepare the investigational product for infusion. The investigational agent infusions will be prepared in identical infusion bags and labeled with the identical investigational drug labels as to preserve the blind. The designated technicians in the ISCI Cell Processing Laboratory (CPL) or designee will be responsible for maintaining the investigational product records including randomized treatment assignments by subject identification.

Primary Purpose: Treatment

• Condition: Ischemic Heart Disease

Intervention

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 1.6 million cells/min. The product will be infused into vein via intravenous line placed in the arm.

Study Arms

• Placebo Comparator: control group
  Four doses of vehicle (Plasma-Lyte A supplemented with 1% HSA) will be given 2 months apart. Each dose will be infused IV at a rate of 1 ml/min for a total of 60 ml over 60 minutes.
  Intervention: Biological: umbilical cord-derived mesenchymal stromal cells (UC-MSCs)
• Experimental: single-dose group
  One dose of UC-MSCs (100 x 106 cells) will be infused IV at a rate of 1 ml/min for a total of 60 ml over 60 minutes (1.6 million cells/ml/min). This will be followed by three IV infusions of placebo (same volume and rate) 2, 4, and 6 months later.
  Intervention: Biological: umbilical cord-derived mesenchymal stromal cells (UC-MSCs)
• Experimental: repeated-dose group
  Four doses of UC-MSCs (100 x 106 cells each) will be given 2 months apart. Each dose will be infused IV at a rate of 1 ml/min for a total of 60 ml over 60 minutes (1.6 million cells/ml/min).
  Intervention: Biological: umbilical cord-derived mesenchymal stromal cells (UC-MSCs)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 17, 2023): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 1, 2026
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

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) 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 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 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 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
   • 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 5 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Roberto Bolli, MD; 502-608-5426; rbolli@louisville.edu

Contact: Michelle Unseld, RN; 502-540-3423; michelle.unseld@louisville.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT06145035
• Other Study ID Numbers: 23.0712; 1369707 ( Other Grant/Funding Number: United States Department of Defence )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Roberto Bolli, University of Louisville
• Original Responsible Party: Same as current
• Current Study Sponsor: Roberto Bolli
• Original Study Sponsor: Same as current

Collaborators

• University of Miami
• University of Texas
• United States Department of Defense

Investigators

• Principal Investigator: Roberto Bolli, MD; University of Louisville School of Medicine

• PRS Account: University of Louisville
• Verification Date: March 2024