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SAFETY & EFFICACY OF INTRAMYOCARDIAL INJECTION OF MESENCHYMAL PRECURSOR CELLS ON MYOCARDIAL FUNCTION IN LVAD RECIPIENTS

Description

This trial is being conducted within the Cardiothoracic Surgical Trials Network of which USC is a Core Clinical Site (NIH Grant 5UM1HL117924, PI Bowdish ME). The network is sponsored by the NIH, NHLBI, NINDS, Canadian Health Institute, and the Cell Therapy Network. Left ventricular assist devices (LVADS) have well-documented survival and quality of life benefits in patients with advanced heart failure for both bridge to transplantation (BTT) and as long-term therapy, so called Destination Therapy (DT) in patients who are not transplant candidates. While some LVAD recipients do recover myocardial function, the occurrence of this event is relatively rare. One method suggested to remodel or regenerate the failed myocardium and potentially allow the ability to remove the LVAD is the use of stem cells injected prior to or at the time of LVAD implantation. Recent pre-clinical and clinical evidence suggests that myocardial transplantation of allogenic mesenchymal stem cells can enhance cardiac performance in settings of acute and chronic functional impairment. The purpose of this study is to evaluate the safety and efficacy of intramyocardial injection of mesenchymal precursor cells (MPCs) on myocardial function in recipients of left ventricular assist devices. MPCs obtained from healthy donors are obtained from a commercial vendor, immunoselected, and expanded ex vivo in a Good Manufacturing Practice facility (Mesoblast, Inc.) and cryopreserved until use under an FDA IDE. The primary objectives of this trial are to evaluate the safety and efficacy of injecting MPCs (150 million dose) into the native myocardium of LVAD recipients.The secondary objectives are to explore the functional and physiologic effects of injecting MPCs (150 million dose) into the native myocardium of LVAD recipients.Patients with advanced heart failure, who are to undergo implantation of an FDA approved LVAD as either BTT or DT will be eligible to participate in the trial. The trial is multicenter. Patients will be enrolled in a single dose cohort randomized in a 2:1 allocation to intramyocardial injection of study product or control (cryoprotective media alone) at the time of LVAD implantation: - Group 1 (n=106): 150 million allogeneic MPCs (Mesoblast, Inc) - Group 2 (n=53): PlaceboA total of 159 subjects will be enrolled throughout all sites, with 6 subjects expected at USC. The primary safety endpoint is the incidence of study intervention-related adverse events (i.e., infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization).The primary efficacy endpoint is the number of temporary weans from LVAD support tolerated over 6 months following randomization. LVAD weans will be conducted at the following time points post LVAD implant: 60 & 90 days, 4, 6, 9 and 12 months (or until transplant, whichever comes first)Multiple secondary endpoints are included including all adverse events, 6 minute walk tests, ability to wean from LVAD support, physiologic and echocardiographic assessments, pathology at heart explant (if explanted for recovery or transplant), quality of life, neurocognition, length of stay, repeat hospitalizations, and resource utilization. All patients will be followed until cardiac transplantation or 24 months post randomization, whichever comes first. A Bayesian approach based on the posterior distribution that active therapy is superior to control will be used to assess the strength of potential efficacy.

Phase

Other

Inclusion and Exclusion Criteria

  • Signed informed consent, inclusive of release of medical information, and Health Insurance Portability and Accountability Act (HIPAA) documentation
  • Age 18 years or older
  • If the subject or partner is of childbearing potential, he or she must be willing to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening and for a period of at least 16 weeks after procedure
  • Female subjects of childbearing potential must have a negative serum pregnancy test at screening
  • Admitted to the clinical center at the time of randomization
  • Clinical indication and accepted candidate for implantation of an FDA-approved (US sites only) or Health Canada-approved (Canadian sites only) implantable, non-pulsatile LVAD as a bridge to transplantation or for destination therapy.

  • Planned percutaneous LVAD implantation
  • Anticipated requirement for biventricular mechanical support
  • Concomitant arrhythmia ablation at time of LVAD implantation -
  • Planned aortic valve intervention for aortic insufficiency at the time of LVAD implantation
  • Cardiothoracic surgery within 30 days prior to randomization
  • Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as unstable plaque rupture, erosion or dissection within 30 days prior to randomization
  • Prior cardiac transplantation, LV reduction surgery, or cardiomyoplasty
  • Acute reversible cause of heart failure (e.g. myocarditis, profound hypothyroidism)
  • Stroke within 30 days prior to randomization
  • Platelet count < 100,000/ul within 24 hours prior to randomization
  • Acute infectious process: acute bacterial, fungal, or viral disease OR acute exacerbation of chronic infectious disease such as hepatitis
  • Presence of >10% anti-HLA antibody titers with known specificity to MPC donor HLA antigens
  • A known hypersensitivity to dimethyl sulfoxide (DMSO), murine, and/or bovine products
  • History of a known active malignancy within the past 3 years except for localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively treated
  • Presence of human immunodeficiency virus (HIV)
  • Received investigational intervention within 30 days prior to randomization
  • Treatment and/or an incomplete follow-up treatment of any investigational cell based therapy within 6 months prior to randomization
  • Active participation in other research therapy for cardiovascular repair/regeneration
  • Prior recipient of stem precursor cell therapy for cardiac repair
  • Pregnant or breastfeeding at time of randomization.
  • History of known or suspected hypercoagulable state in the opinion of the investigator

Sites

Please contact Tammie Possemato to learn more about where you can participate in this trial. Please use the contact form on the right side.

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