The TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (The TRIDENT Study) (Trident)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Miami
Sponsor:
Collaborator:
The EMMES Corporation
Information provided by (Responsible Party):
Joshua M Hare, University of Miami
ClinicalTrials.gov Identifier:
NCT02013674
First received: December 2, 2013
Last updated: July 11, 2014
Last verified: July 2014
  Purpose

Thirty (30) patients with chronic ischemic left ventricular dysfunction secondary to MI scheduled to undergo cardiac catheterization will be enrolled in the study.This is a phase II study intended to gain additional safety and efficacy assessments among two dose levels previously studied in a phase I setting. In this study, a 20 million total hMSC dose and a 100 million total hMSC dose will be randomly allocated administered via the Biocardia Helical infusion system in a blinded manner.

The technique of transplanting progenitor cells into a region of damaged myocardium, termed cellular cardiomyoplasty1, is a potentially new therapeutic modality designed to replace or repair necrotic, scarred, or dysfunctional myocardium2-4. Ideally, graft cells should be readily available, easy to culture to ensure adequate quantities for transplantation, and able to survive in host myocardium, which is often a hostile environment of limited blood supply and immunorejection. Whether effective cellular regenerative strategies require that administered cells differentiate into adult cardiomyocytes and couple electromechanically with the surrounding myocardium is increasingly controversial and recent evidence suggests that this may not be required for effective cardiac repair. Most importantly, transplantation of graft cells should improve cardiac function and prevent adverse ventricular remodeling. To date, a number of candidate cells have been transplanted in experimental models, including fetal and neonatal cardiomyocytes5, 6, embryonic stem cell-derived myocytes5, 7, 8, tissue engineered contractile grafts9, skeletal myoblasts10, 11, several cell types derived from adult bone marrow12-20, and cardiac precursors residing within the heart itself21-23. There has been substantial clinical development in the use of whole bone marrow and skeletal myoblast preparations in studies enrolling both post-infarction patients and patients with chronic ischemic left ventricular dysfunction and heart failure. The effects of bone marrow-derived mesenchymal stem cells (MSCs) have also been studied clinically24, 25.

Currently, bone marrow or bone marrow-derived cells represent a highly promising modality for cardiac repair. The totality of evidence from trials investigating autologous whole bone marrow infusions into patients following myocardial infarction supports the safety of this approach. In terms of efficacy, increases in ejection fraction are reported in the majority of the trials.

Chronic ischemic left ventricular dysfunction is a common and problematic condition; definitive therapy in the form of heart transplantation is available to only a tiny minority of eligible patients. Cellular cardiomyoplasty for chronic heart failure has been studied less than for acute MI, but represents a potentially important alternative for this disease.


Condition Intervention Phase
Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction.
Biological: Allogeneic Adult Human Mesenchymal Stem Cells (MSCs)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II, Randomized, Blinded, Study of the Safety and Efficacy of Transendocardial Injection of Allogeneic Human Mesenchymal Stem Cells (hMSCs) (20 Million or 100 Million Total MSCs) in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction.

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Treatment-emergent serious adverse events (SAE). [ Time Frame: One month post-catherization ] [ Designated as safety issue: Yes ]
    Incidence (at one month post-catheterization) of any treatment-emergent serious adverse events, defined as the composite of: death, non-fatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, sustained ventricular arrhythmias (characterized by ventricular arrhythmias lasting longer than 15 seconds or with hemodynamic compromise).


Secondary Outcome Measures:
  • Computed Tomography (CT) derived measures of left ventricular function. [ Time Frame: Participants will be followed once at baseline and once 12 months following injection. ] [ Designated as safety issue: No ]

    Computed Tomography (CT) derived measures of left ventricular function:

    1. Difference between the baseline and 12-month infarct scar size as determined by delayed contrast-enhanced CT
    2. Difference between the baseline and 12-month regional left ventricular function (at the site of allogeneic cell injections) as determined by CT.
    3. Difference between the baseline and 12-month regional left ventricular wall thickening as determined by CT.
    4. Difference between the baseline and 12-month left ventricular end diastolic wall thickness as determined by CT.
    5. Difference between the baseline and 12-month left ventricular ejection fraction, end diastolic and end systolic volumes, as determined by CT.
    6. Difference between the baseline and 12-month left ventricular regional myocardial perfusion as determined by CT.

  • Tissue perfusion measured by Computed Tomography (CT). [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    Tissue perfusion measured by CT.

  • Peak Oxygen Consumption (VO2) (by treadmill determination). [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    Peak VO2 (by treadmill determination).

  • Six-minute walk test. [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    Six-minute walk test.

  • New York Heart Association functional class. [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    New York Heart Association functional class.

  • Major Adverse Cardiac Events (MACE) [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    Incidence of the Major Adverse Cardiac Events (MACE) endpoint, defined as the composite incidence of (1) death, (2) hospitalization for worsening heart failure, or (3) non-fatal recurrent MI.

  • Secondary safety endpoints. [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: Yes ]

    The following safety endpoints will be evaluated in this trial (during the six-month follow-up period, at the month 12 visit:

    • Treatment emergent adverse event (AE) rates.
    • 24-hour ambulatory electrocardiogram (ECG) recordings.
    • Hematology and clinical chemistry values and urinalysis results.
    • Serial Troponin I and creatine kinase, muscle and brain (CK-MB) values (every 12 hours for the first 24 hours post-cardiac catheterization).
    • Post-cardiac catheterization echocardiogram.

  • Minnesota Living with Heart Failure (MLHF)Questionnaire [ Time Frame: Participants will be followed once every 6 months following injection for an expected average of 12 months. ] [ Designated as safety issue: No ]
    Minnesota Living with Heart Failure (MLHF)Questionnaire

  • Echocardiographic-derived measures of left ventricular function [ Time Frame: Participants will be followed for three visits, over an expected average of 12 months. ] [ Designated as safety issue: No ]
    Difference between the baseline, 6-month, and 12-month left ventricular end diastolic wall thickness as determined by echocardiogram.


Estimated Enrollment: 30
Study Start Date: November 2013
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimental: Treatment Group 1
Fifteen (15) patients to be treated with Allo-hMSCs: 4 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 0.2x 10^8 (20 million) Allo-hMSCs.
Biological: Allogeneic Adult Human Mesenchymal Stem Cells (MSCs)
Experimental: Experimental: Treatment Group 2
Fifteen (15) patients to be treated with Allo-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1x 10^8 (100 million) Allo-hMSCs.
Biological: Allogeneic Adult Human Mesenchymal Stem Cells (MSCs)

  Eligibility

Ages Eligible for Study:   21 Years to 89 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • In order to participate in this study, a patient MUST:

    1. Be ≥ 21 and < 90 years of age.
    2. Provide written informed consent.
    3. Have a diagnosis of chronic ischemic left ventricular dysfunction secondary to myocardial infarction (MI) as defined by previous myocardial infarction documented by an imaging study demonstrating coronary artery disease with corresponding areas of akinesis, dyskinesis, or severe hypokinesis.
    4. Been treated with appropriate maximal medical therapy for heart failure or post-infarction left ventricular dysfunction. For beta-blockade, the patient must have been on a stable dose of a clinically appropriate beta-blocker for 3 months. For angiotensin-converting enzyme inhibition, the patient must have been on a stable dose of a clinically appropriate agent for 1 month.
    5. Be a candidate for cardiac catheterization within 5 to 10 weeks of screening as determined by doctors.
    6. Have an ejection fraction of less than or equal to 50% by gated blood pool scan, two-dimensional echocardiogram, CT, or left ventriculogram within the prior six months and not in the setting of a recent ischemic event.

Exclusion Criteria:

  • In order to participate in this study, a patient MUST NOT:

    1. Have a baseline glomerular filtration rate ≤ 35 ml/min/1.73m2.
    2. Have a known, serious radiographic contrast allergy.
    3. Have a Mechanical aortic valve or heart constrictive device.
    4. Have a documented presence of aortic stenosis (aortic stenosis graded as 1.5cm2 or less).
    5. Have a documented presence of moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as ≥+2).
    6. Require coronary artery revascularization. Patients who require or undergo revascularization procedures should undergo these procedures a minimum of 3 months in advance of treatment in this study. In addition, patients who develop a need for revascularization following enrollment will be submitted for this therapy without delay.
    7. Have 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) or Corrected for heart rate (QTc) interval > 550 ms on screening ECG
    8. Automatic Implantable Cardioverter Defibrillator (AICD) firing in the past 60 days prior to enrollment.
    9. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/µl or platelet values < 100,000/µl without another explanation.
    10. Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater than three times the upper limit of normal (ULN).
    11. Have a coagulopathy = (INR > 1.3) not due to a reversible cause (i.e., Coumadin). Patients on Coumadin will be withdrawn 5 days before the procedure and confirmed to have an INR < 1.3. Patients who cannot be withdrawn from Coumadin will be excluded from enrollment
    12. Have known allergies to penicillin or streptomycin.
    13. Hypersensitivity to Dimethyl Sulfoxide (DMSO).
    14. Be an organ transplant recipient.
    15. Have a history of organ or cell transplant rejection
    16. Have a clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma.
    17. Have a non-cardiac condition that limits lifespan to < 1 year.
    18. Have a history of drug or alcohol abuse within the past 24 months.
    19. Be on chronic therapy with immunosuppressant medication, such as corticosteroids or TNFα antagonists.
    20. Be serum positive for HIV, hepatitis BsAg or viremic hepatitis C.
    21. Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial.
    22. Be a female who is pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods. Female patients must undergo a blood or urine pregnancy test at screening and within 36 hours prior to injection.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02013674

Locations
United States, Florida
ISCI / University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Joshua M Hare, MD    305-243-5579    jhare@med.miami.edu   
Contact: Darcy L DiFede, RN, BSN    305-243-9106    ddifede@med.miami.edu   
Sponsors and Collaborators
Joshua M Hare
The EMMES Corporation
Investigators
Principal Investigator: Joshua M Hare, MD ISCI / University of Miami Miller School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Joshua M Hare, Chief Science Officer, Director of Interdisciplinary Stem Cell Institute, University of Miami
ClinicalTrials.gov Identifier: NCT02013674     History of Changes
Other Study ID Numbers: 20120660
Study First Received: December 2, 2013
Last Updated: July 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami:
Cardiovascular, Chronic Ischemic Left Ventricular Dysfunction

Additional relevant MeSH terms:
Infarction
Neoplasm Metastasis
Ischemia
Myocardial Infarction
Ventricular Dysfunction
Ventricular Dysfunction, Left
Pathologic Processes
Necrosis
Neoplastic Processes
Neoplasms
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on September 16, 2014