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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04476901
Recruitment Status : Recruiting
First Posted : July 20, 2020
Last Update Posted : May 14, 2021
Sponsor:
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

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

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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


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




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



Information from the National Library of Medicine

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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 at the time of signing the informed consent form.
  2. Diagnosis of NIDCM with left ventricular ejection fraction ≤40%. Note: a left ventricular end diastolic diameter (LVEDD) ≥ 5.9cm in male subjects, an LVEDD of ≥ 5.6cm in female subjects, or left ventricular end diastolic volume index ≥ 125 mL/m2 (in either sex).
  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) mechanical or bioprosthetic left heart valve (mitral clip will be excluded); or 2) severe left-sided valvular (mital or 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 any known toxin (e.g amyloid, anthracycline)
  8. Evidence of a life-threatening arrhythmia in the absence of a defibrillator (non-sustained ventricular tachycardia ≥ 20 consecutive beats or complete second or third-degree heart block in the absence of a functioning pacemaker) within 30 days of consent or the measure of the time interval between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QTc) interval > 550 ms on baseline electrocardiogram (ECG).
  9. Automated Implantable Cardioverter Defibrillator (AICD) appropriate firing or anti tachycardia pacing for ventricular fibrillation within 30 days prior to consent.
  10. Have an estimated baseline glomerular filtration rate <35 ml/min/1.73m2
  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 2 years (i.e., subjects with prior malignancy must be disease free for 2 years), except curatively treated basal cell or squamous cell carcinoma or cervical carcinoma.
  17. 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 24 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 allergies 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. Any other condition that in the judgment of the Investigator would be a contraindication to enrollment or follow-up.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04476901


Contacts
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Contact: Shelly L Sayre, MPH 713-500-9529 Shelly.L.Sayre@uth.tmc.edu
Contact: Yvenie Desire 305-243-7273 ydesire@miami.edu

Locations
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United States, California
Stanford University Recruiting
Stanford, California, United States, 94304
Contact: Fouzia Khan, MBBS    650-736-1410    fouziak@stanford.edu   
Contact: Banu Priya Rajasekaran, MBBS    650-721-6092    bpriya@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 Not yet 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: Gabrielle Phillip    832-355-9614    gphillip@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
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Principal Investigator: Joshua Hare, MD University of Miami
Additional Information:
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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    Key Record Dates
Last Update Posted: May 14, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Cardiomyopathies
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases
Cardiomegaly