Administration of Allogeneic-MSC in Patients With Non-Ischemic Dilated Cardiomyopathy (DCMII)

A Phase IIB Randomized, Placebo-Controlled, Multicenter Study of the Comparative Efficacy and Safety of Administration of Allogeneic-MSC Versus Placebo in Patients With Non- Ischemic Dilated Cardiomyopathy

The purpose of this study is to evaluate the safety and effectiveness of an experimental drug called human allogeneic mesenchymal stem cell therapy.

Study Overview

• Status: Recruiting
• Conditions: Non-ischemic Dilated Cardiomyopathy
• Intervention / Treatment: Other: Placebo; Biological: allogeneic human mesenchymal stem cells (hMSCs)

• Study Type: Interventional
• Enrollment (Estimated): 136
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shelly L Sayre, MPH; Phone Number: 713-500-9529; Email: Shelly.L.Sayre@uth.tmc.edu
• Study Contact Backup: Name: Lina Caceres; Phone Number: 305-243-5399; Email: lvc25@med.miami.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94304
      • Recruiting
      • Stanford University
      • Contact: Fouzia Khan, MBBS; Phone Number: 650-736-1410; Email: fouziak@stanford.edu
      • Contact: Ashwini Narayana; Email: ashwinil@stanford.edu
      • Principal Investigator: Phil Yang, MD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami Miller School of Medicine
      • Contact: Lina Caceres; Phone Number: 305-243-5399; Email: lvc25@med.miami.edu
      • Contact: Jairo Tovar; Phone Number: 305-243-5399; Email: jat243@med.miami.edu
      • Principal Investigator: Josh Hare, MD
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University Of Louisville
      • Contact: Heidi Wilson; Phone Number: 502-540-3721; Email: heidi.wilson@louisville.edu
      • Principal Investigator: Roberto Bolli, MD
      • Contact: Michelle Unseld; Phone Number: 502-540-3423; Email: michelle.unseld@louisville.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Heart Institute
      • Contact: Nichole Piece; Phone Number: 832-355-9173; Email: npiece@texasheart.org
      • Contact: Sylvia Carranza; Phone Number: 832-355-8524; Email: SCarranza@texasheart.org
      • Principal Investigator: Emerson Perin, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Men and women aged 18 to 80 years (inclusive) at the time of signing the informed consent form.
2. Diagnosis of NIDCM with left ventricular ejection fraction ≤45%.
3. Appropriate guideline-directed optimal medical therapy for non-ischemic cardiomyopathy. At a minimum, subjects must be on beta blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) or Angiotensin Receptor Neprilysin Inhibitors (ARNI) or have appropriate medical indication precluding use of one or both of these agents. Subjects must be on a stable regimen for at least 30 days prior to the procedure. Dose titration is allowed.
4. Be a candidate for cardiac catheterization*
5. Be willing to undergo DNA test.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Be eligible for or require standard-of-care surgical or percutaneous intervention for the treatment of non-ischemic dilated cardiomyopathy
2. Clinical manifestation of coronary artery disease (CAD) (e.g., chest pain and concomitant clinical findings such as electrocardiogram changes suggestive of coronary ischemia, myocardial infarction) or evidence of endocardial or transmural scar on cardiac MRI suggestive of undiagnosed CAD or history of percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Be indicated for or require coronary artery revascularization
3. Documented presence of epicardial stenosis of 70% or greater in one or more major epicardial coronary arteries
4. Valvular heart disease including 1) aortic valve prosthesis, mechanical mitral valve, and mitral valve clip; 2) severe aortic valve insufficiency/regurgitation within 12 months of consent*
5. Aortic stenosis with valve area ≤ 1.5cm2*
6. Cardiomyopathy due to acute Post-partum (within 6 months), Non-compaction*, or Hypertrophic* cardiomyopathy
7. Cardiomyopathy due to known toxin (e.g amyloid) Note: anthracycline induced cardiomyopathy will be allowed
8. QTc interval > 550 ms on baseline electrocardiogram (ECG) (note: QTc interval is the interval between the start of the Q wave and the end of the T wave in the heart's electrical cycle)
9. Automated Implantable Cardioverter Defibrillator (AICD) appropriate firing or anti tachycardia pacing for ventricular tachycardia or ventricular fibrillation within 30 days prior to consent
10. Have an estimated baseline glomerular filtration rate below the clinical site's institutional cutoff
11. A hematologic abnormality during baseline testing as evidenced by hemoglobin < 9 g/dl; hematocrit < 30%; absolute neutrophil count < 2,000 or total WBC count more than 2 times upper limit of normal; or platelet values < 100,000/ul
12. Have liver dysfunction, as evidenced by enzymes Aspartate Transaminase Enzyme (AST) and Alanine Aminotransferase Enzyme (ALT) greater than three times the ULN
13. Have a bleeding diathesis or coagulopathy (International Normalised Ratio (INR) > 1.5), cannot be withdrawn from anticoagulation therapy, or will refuse blood transfusions
14. Be a solid organ transplant recipient. This does not include prior cell based therapy (>12 months prior to enrollment), bone, skin, ligament, tendon or corneal grafting.
15. Have a history of organ or cell transplant rejection
16. Have a clinical history of malignancy within the past 12 months (i.e., subjects with prior malignancy must be disease free for 12 months), except curatively treated basal cell or squamous cell carcinoma or cervical carcinoma
17. Drug and/or alcohol abuse or dependence within the past 9 months
18. Be serum positive for HIV, hepatitis B surface antigen, or viremic hepatitis C
19. Documented presence of a known Left Ventricular (LV) thrombus, aortic dissection, or aortic aneurysm. (Refer to "Guidance to the PI" section with regards to LV thrombus, below)*
20. Blood glucose levels (HbA1c) >10%
21. Severe radiographic contrast allergy
22. Known history of anaphylactic reaction to penicillin or streptomycin
23. Hypersensitivity to dimethyl sulfoxide (DMSO)
24. Non-cardiac condition with life expectancy < 1 year
25. Acute stroke or transient ischemic attack within 3 months of enrollment
26. Be pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods
27. Pacemaker-dependence with an Implantable Cardioverter Defibrillator (ICD) (Note: pacemaker-dependent candidates without an ICD are not excluded)

28. Presence of a pacemaker and/or 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
29. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent
30. Other MRI contraindications (e.g. subject body habitus incompatible with MRI)
31. Need for advanced heart failure therapy (e.g. IV inotropes)
32. Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial
33. Any other condition that in the judgment of the Investigator would be a contraindication to enrollment or follow-up

(*) Applies to subjects receiving product via transendocardial administration only

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Genotype A administered with placebo Group; Participants whose blood genotyping resulted with Genotype A (absence of any variant/ presence of benign variant) and randomized to the placebo group will receive the placebo intervention.	Other: Placebo; Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)
Experimental: Genotype A administered with hMSC Group; Participants whose blood genotyping resulted with Genotype A (absence of any variant/ presence of benign variant) and randomized to the treatment group will receive the hMSC intervention.	Biological: allogeneic human mesenchymal stem cells (hMSCs); allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).
Placebo Comparator: Genotype B administered with placebo Group; Participants whose blood genotyping resulted with Genotype B (variants of uncertain significance) and randomized to the placebo group will receive the placebo intervention.	Other: Placebo; Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)
Experimental: Genotype B administered with hMSC Group; Participants whose blood genotyping resulted with Genotype B (variants of uncertain significance) and randomized to the treatment group will receive the hMSC intervention.	Biological: allogeneic human mesenchymal stem cells (hMSCs); allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).
Placebo Comparator: Genotype C administered with placebo Group; Participants whose blood genotyping resulted with Genotype C (pathogenic or likely pathogenic variants) and randomized to the placebo group will receive the placebo intervention.	Other: Placebo; Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)
Experimental: Genotype C administered with hMSC Group; Participants whose blood genotyping resulted with Genotype C (pathogenic or likely pathogenic variants) and randomized to the treatment group will receive the hMSC intervention.	Biological: allogeneic human mesenchymal stem cells (hMSCs); allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in LVEF	Change in Left Ventricular Ejection Fraction (LVEF) as assessed via cardiac Magnetic Resonance Imaging (MRI)	Baseline, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in global ventricular strain	Change in global ventricular strain as assessed via cardiac Harmonic Phase (HARP) MRI	Baseline, 12 months
Change in left regional strain	Change in regional ventricular strain as assessed via cardiac HARP MRI	Baseline, 12 months
Left ventricular function concordance	The left ventricular function concordance will be measured as the Number of individuals who experienced an increase in left ventricular ejection fraction (LVEF) and a simultaneous decrease in both left ventricular end systolic volume index (LVESVI) and left ventricular end diastolic volume index (LVEDVI)	12 months
Change in LVEDVI	Change in left ventricular end diastolic index (LVEDVI) as assessed via cardiac MRI	Baseline, 12 months
Change in LVESVI	Change in left ventricular end systolic index (LVESVI) as assessed via cardiac MRI	Baseline, 12 months
Change in Maximal oxygen consumption (peak VO2)	Change in maximal oxygen consumption (peak VO2) as assessed via treadmill	Baseline, 12 months
Change in Exercise tolerance	Change in exercise tolerance as assessed as the distance covered via the six-minute walk test	Baseline, 12 months
Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) Score	Minnesota Living with Heart Failure Questionnaire (MLHFQ) is a 21-item questionnaire with a total score ranging from 0 to 105 with lower scores indicative of better outcome.	Baseline, 12 months
Change in New York Heart Association (NYHA) Class	NYHA Classifications of heart failure are as follows: Class I (no limitations); Class II (mild symptoms); Class III (marked limitations); Class IV (Severe limitations)	Baseline, 12 months
Percent change in flow mediated diameter	Change in endothelial function will be reported as the percent change in flow mediated diameter assessed via flow mediated dilation (FMD).	Baseline, 12 months
Change in EPC-CFU	Change in endothelial function will be reported as the change in Endothelial Progenitor Cell Colony Forming Unit (EPC-CFU) assessed via blood sample assay	Baseline, 12 months
Change in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)	Change in NT-proBNP as assessed via blooddraw	Baseline, 12 months
Change in cytokines	Change in NT-proBNP as assessed via blooddraw	Baseline, 12 months
Incidence of MACE	Safety will be reported as the incidence of Major Adverse Cardiac Events (MACE) assessed by treating physician	12 months
Incidence of TE-SAEs	Safety will be reported as the incidence of Treatment Emergent Serious Adverse Events (TE-SAEs) assessed by treating physician	Day 30

Collaborators and Investigators

• Sponsor: Joshua M Hare
• Collaborators: The University of Texas Health Science Center, Houston; United States Department of Defense
• Investigators: Principal Investigator: Joshua Hare, MD, University of Miami

Publications and helpful links

Helpful Links

• Cardiovascular Cell Therapy Research Network
• Information on stem cells from the National Institutes of Health
• DCM II Trial

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2021
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 15, 2020
• First Submitted That Met QC Criteria: July 15, 2020
• First Posted (Actual): July 20, 2020

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Bone marrow-derived mesenchymal stem cells; Allogeneic mesenchymal stem cells
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: 20200566; CDMRP-PR191597 (Other Grant/Funding Number: US Department of Defense); 20-02-134 (Other Identifier: BRANY IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No