Cardiomyopathy, Heart Failure, Ventricular Dysfunction
Conditions
Keywords
Heart Failure, Left Ventricular Assist Device, Heart Transplantation, Cardiomyopathy, Destination Therapy, Cell Therapy
Brief summary
The main purpose of this research is to determine whether injecting mesenchymal precursor cells (MPC) into the heart during surgery to implant a left ventricular assist device (LVAD) is safe. MPCs are normally present in human bone marrow, and have been shown to increase the development of blood vessels and new heart muscle cells in the heart. In addition, this research is being done to test whether injecting the MPCs into the heart is effective in improving heart function.
Detailed description
Intramyocardial injection of mesenchymal precursor cells (MPC) in patients with advanced heart failure who are treated with left ventricular assist device (LVAD) implantation may result in a renewable source of proliferating functional cardiomyocytes, as well as induce development of capillaries and larger size blood vessels to supply oxygen and nutrients to endogenous myocardium and newly-implanted cardiomyocytes, and release factors capable of paracrine signaling. If safety is established and an efficacy signal is observed in this exploratory trial, then the investigators will design a follow-up trial (stage 2) based on an adaptive design. The next trial would randomize patients to active therapy at one of two doses (25 and 75 million MPCs) versus placebo, and based on a predetermined selection criterion drop randomization to one of the dose arms as results accrue. Should this exploratory trial demonstrate safety but no signal of efficacy, then the subsequent trial would be based on a single dose of 75 million MPCs versus placebo.
Interventions
BIOLOGICALMPC Intramyocardial injection
Intramyocardial injection of 25 million mesenchymal precursor cells at the time of LVAD implantation
BIOLOGICALControl Solution
Injection of control solution during the LVAD implantation.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Deborah Ascheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 implantable, non-pulsatile LVAD as a bridge to transplantation or for destination therapy.
Exclusion criteria
* Planned percutaneous LVAD implantation; * Anticipated requirement for biventricular mechanical support; * Cardiothoracic surgery within 30 days prior to randomization; * Myocardial infarction 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; * Active systemic infection within 48 hours prior to randomization; * Presence of \>10% anti-human leukocyte antigen (anti-HLA) antibody titers with known specificity to the MPC donor HLA antigens; * A known hypersensitivity to dimethyl sulfoxide (DMSO), murine, and/or bovine products; * History of cancer prior to screening (excluding basal cell carcinoma); * Acute or chronic infectious disease, including but not limited to human immunodeficiency virus (HIV); * Received investigational intervention within 30 days prior to randomization; * Treatment and/or an incompleted 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intervention Related Adverse Events | 90 days | The primary safety endpoint of this study is the incidence of the following potential study-intervention related adverse events within 90 days post intervention (LVAD implantation + intramyocardial injection of study product): infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Status and Ventricular Function | 90 days | The key efficacy endpoint of this study is functional status and ventricular function, while weaned from LVAD support, at 90 days post intervention (LVAD implantation + intramyocardial injection of study product). Functional status is defined by the ability to tolerate wean from LVAD support for 30 minutes without signs or symptoms of hypoperfusion, including, but not limited to symptoms of low output or signs of vascular congestion. Ventricular function will be assessed by transthoracic echocardiogram (TTE) in those patients able to be weaned for 30 minutes from LVAD support. The number of participants who successfully tolerated the 30 minute wean from LVAD support at 90 days is reported. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted in 11 U.S. centers with a Data and Clinical Coordinating Center (DCC); International Center for Health Outcomes and Innovation Research \[InCHOIR\], Icahn School of Medicine at Mount Sinai under an investigational new drug application. Enrollment began in May 2012, and the last patient was enrolled in August 2012.
Participants by arm
| Arm | Count |
|---|---|
| MPC Intramyocardial Injection Intramyocardial injections of 25 million MPCs
Mesenchymal Precursor Cell Injection: Intramyocardial injection of 25 million mesenchymal precursor cells at the time of LVAD implantation | 20 |
| Control Solution Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO
50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO: Injection of control solution during the LVAD implantation. | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | MPC Intramyocardial Injection | Control Solution | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 15.4 | 62.2 years STANDARD_DEVIATION 7.8 | 57.4 years STANDARD_DEVIATION 13.6 |
| Cardiomyopathy Ischemic | 7 participants | 4 participants | 11 participants |
| Cardiomyopathy Non-Ischemic | 13 participants | 6 participants | 19 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 10 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Indication for LVAD Bridge to Transplantation | 7 participants | 3 participants | 10 participants |
| Indication for LVAD Destination Therapy | 13 participants | 7 participants | 20 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 8 Participants | 22 Participants |
| Region of Enrollment United States | 20 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 17 Participants | 8 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 20 | 4 / 10 |
| serious Total, serious adverse events | 19 / 20 | 9 / 10 |
Outcome results
Primary
Intervention Related Adverse Events
The primary safety endpoint of this study is the incidence of the following potential study-intervention related adverse events within 90 days post intervention (LVAD implantation + intramyocardial injection of study product): infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MPC Intramyocardial Injection | Intervention Related Adverse Events | 0 events |
| Control Solution | Intervention Related Adverse Events | 0 events |
Secondary
Functional Status and Ventricular Function
The key efficacy endpoint of this study is functional status and ventricular function, while weaned from LVAD support, at 90 days post intervention (LVAD implantation + intramyocardial injection of study product). Functional status is defined by the ability to tolerate wean from LVAD support for 30 minutes without signs or symptoms of hypoperfusion, including, but not limited to symptoms of low output or signs of vascular congestion. Ventricular function will be assessed by transthoracic echocardiogram (TTE) in those patients able to be weaned for 30 minutes from LVAD support. The number of participants who successfully tolerated the 30 minute wean from LVAD support at 90 days is reported.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MPC Intramyocardial Injection | Functional Status and Ventricular Function | 10 participants |
| Control Solution | Functional Status and Ventricular Function | 2 participants |