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

• ClinicalTrials.gov Identifier: NCT04476901
• Recruitment Status: Recruiting
• First Posted: July 20, 2020
• Last Update Posted: October 26, 2022
• Sponsor: Joshua M Hare
• Collaborators: United States Department of Defense; The University of Texas Health Science Center, Houston
• Information provided by (Responsible Party): Joshua M Hare, University of Miami

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Non-ischemic Dilated Cardiomyopathy	Biological: allogeneic human mesenchymal stem cells (hMSCs); Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIB Randomized, Placebo-Controlled, Multicenter Study of the Comparative Efficacy and Safety of Transendocardial Injection of Allogeneic-MSC Versus Placebo in Patients With Non- Ischemic Dilated Cardiomyopathy
• Actual Study Start Date: May 7, 2021
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

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
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
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
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
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
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

Outcome Measures

Primary Outcome Measures :

1. Change in LVEF [ Time Frame: Baseline, 12 months ]
   Change in Left Ventricular Ejection Fraction (LVEF) as assessed via cardiac Magnetic Resonance Imaging (MRI)

Secondary Outcome Measures :

1. Change in global ventricular strain [ Time Frame: Baseline, 12 months ]
   Change in global ventricular strain as assessed via cardiac Harmonic Phase (HARP) MRI
2. Change in left regional strain [ Time Frame: Baseline, 12 months ]
   Change in regional ventricular strain as assessed via cardiac HARP MRI
3. Left ventricular function concordance [ Time Frame: 12 months ]
   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)
4. Change in LVEDVI [ Time Frame: Baseline, 12 months ]
   Change in left ventricular end diastolic index (LVEDVI) as assessed via cardiac MRI
5. Change in LVESVI [ Time Frame: Baseline, 12 months ]
   Change in left ventricular end systolic index (LVESVI) as assessed via cardiac MRI
6. Change in Maximal oxygen consumption (peak VO2) [ Time Frame: Baseline, 12 months ]
   Change in maximal oxygen consumption (peak VO2) as assessed via treadmill
7. Change in Exercise tolerance [ Time Frame: Baseline, 12 months ]
   Change in exercise tolerance as assessed as the distance covered via the six-minute walk test
8. Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) Score [ Time Frame: Baseline, 12 months ]
   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.
9. Change in New York Heart Association (NYHA) Class [ Time Frame: Baseline, 12 months ]
   NYHA Classifications of heart failure are as follows: Class I (no limitations); Class II (mild symptoms); Class III (marked limitations); Class IV (Severe limitations)
10. Percent change in flow mediated diameter [ Time Frame: Baseline, 12 months ]
    Change in endothelial function will be reported as the percent change in flow mediated diameter assessed via flow mediated dilation (FMD).
11. Change in EPC-CFU [ Time Frame: Baseline, 12 months ]
    Change in endothelial function will be reported as the change in Endothelial Progenitor Cell Colony Forming Unit (EPC-CFU) assessed via blood sample assay
12. Change in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Baseline, 12 months ]
    Change in NT-proBNP as assessed via blooddraw
13. Change in cytokines [ Time Frame: Baseline, 12 months ]
    Change in NT-proBNP as assessed via blooddraw
14. Incidence of MACE [ Time Frame: 12 months ]
    Safety will be reported as the incidence of Major Adverse Cardiac Events (MACE) assessed by treating physician
15. Incidence of TE-SAEs [ Time Frame: Day 30 ]
    Safety will be reported as the incidence of Treatment Emergent Serious Adverse Events (TE-SAEs) assessed by treating physician

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Shelly L Sayre, MPH; 713-500-9529; Shelly.L.Sayre@uth.tmc.edu

Contact: Lina Caceres; 305-243-5399; lvc25@med.miami.edu

Locations

United States, California

Stanford University; Recruiting

Stanford, California, United States, 94304

Contact: Fouzia Khan, MBBS 650-736-1410 fouziak@stanford.edu

Contact: Ashwini Narayana ashwinil@stanford.edu

Principal Investigator: Phil Yang, MD

United States, Florida

University of Miami Miller School of Medicine; Recruiting

Miami, Florida, United States, 33136

Contact: Lina Caceres 305-243-5399 lvc25@med.miami.edu

Contact: Jairo Tovar 305-243-5399 jat243@med.miami.edu

Principal Investigator: Josh Hare, MD

United States, Kentucky

University of Louisville; Recruiting

Louisville, Kentucky, United States, 40202

Contact: Heidi Wilson 502-540-3721 heidi.wilson@louisville.edu

Contact: Julie Caswell 502-587-4177 julie.caswell@louisville.edu

Principal Investigator: Roberto Bolli, MD

United States, Texas

Texas Heart Institute; Recruiting

Houston, Texas, United States, 77030

Contact: Nichole Piece 832-355-9173 npiece@texasheart.org

Contact: Sylvia Carranza 832-355-8524 SCarranza@texasheart.org

Principal Investigator: Emerson Perin, MD, PhD

Sponsors and Collaborators

Joshua M Hare

United States Department of Defense

The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: Joshua Hare, MD; University of Miami

More Information

Additional Information:

Cardiovascular Cell Therapy Research Network 

Information on stem cells from the National Institutes of Health 

DCM II Trial 

• Responsible Party: Joshua M Hare, Principal Investigator, University of Miami
• ClinicalTrials.gov Identifier: NCT04476901
• Other Study ID Numbers: 20200566; CDMRP-PR191597 ( Other Grant/Funding Number: US Department of Defense ); 20-02-134 ( Other Identifier: BRANY IRB )
• First Posted: July 20, 2020
• Last Update Posted: October 26, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Joshua M Hare, University of Miami:

Allogeneic mesenchymal stem cells; Bone marrow-derived mesenchymal stem cells

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Dilated; Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Laminopathies; Genetic Diseases, Inborn