Cardiomyopathy, Heart Failure, Ventricular Dysfunction
Conditions
Keywords
Heart Failure, Left Ventricular Assist Device, Heart Transplantation, Cardiomyopathy, Destination Therapy, Cell Therapy, Bridge to Transplant
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; 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.
Interventions
BIOLOGICALMPC Intramyocardial Injection
Intramyocardial injection of 150 million mesenchymal precursor cells at the time of LVAD implantation
DRUGControl Solution
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Annetine Gelijns
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 (US sites only) or Health Canada-approved (Canadian sites only) 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Temporary Weans From LVAD Support Tolerated | up to 6 months | functional status, defined by the number of temporary weans from LVAD support tolerated over the 6 months post-randomization. A successful wean is the ability to tolerate temporary weaning from LVAD support for 30 minutes without sustained symptoms of worsening heart failure. Wean failures are defined as inability to tolerate the temporary wean for 30 minutes; death; or patient too unstable, in the judgment of the primary heart failure cardiologist, to tolerate the wean attempt. |
| Number of Participants With Adverse Events | up to 6 months | Safety as assessed by number of study intervention-related adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 12 months | — |
| Change in Quality of Life (QoL) | 6 months and 12 months | Quality of life will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), a widely used tool in heart failure populations, and the Short Form 12 (SF12), a widely used overall health status measure. |
| Hopkins Verbal Learning Test | 3 months and 12 months | Cognitive performance will be assessed Hopkins Verbal Learning Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| Trailmaking Tests A and B | 3 months and 12 months | Cognitive performance will be assessed using Trailmaking Tests A and B. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| MCG Complex Figures | 3 months and 12 months | Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| Digit Span | 3 months and 12 months | Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| Physiologic Assessments | up to 12 months | Echocardiographic assessments of the myocardial size and function by transthoracic echocardiography with LVAD at full support, and as tolerated following 6-Minute Walk Test (MWT) while weaned from LVAD support (for patients who tolerate wean from LVAD support for 30 minutes) |
| Controlled Oral Word Association | 3 months and 12 months | Cognitive performance will be assessed using the Controlled Oral Word Association. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| Length of Stay | up to 12 months | Length of stay of index hospitalization |
| Hospitalizations | up to 12 months | Frequency and cause of readmissions |
| Hospital Costs | up to 12 months | Hospital resource use |
| Functional Status | up to 12 months | functional status, defined by the number of temporary weans from LVAD support tolerated |
| Digit Symbol Substitution Test | 3 months and 12 months | Cognitive performance will be assessed using the Digit Symbol Substitution Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel. |
| Histopathological Assessments of Myocardial Tissue | up to 12 months | — |
Countries
Canada, United States
Participant flow
Recruitment details
Screening started in 2014. First patient randomized in July 2015. Last patient randomized in August 2017.
Participants by arm
| Arm | Count |
|---|---|
| MPC Intramyocardial Injection MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells (MPCs) at the time of LVAD implantation | 106 |
| Control Solution Control Solution: Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO | 53 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 8 |
| Overall Study | received transplant | 21 | 14 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Control Solution | Total | MPC Intramyocardial Injection |
|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 11.7 | 56 years STANDARD_DEVIATION 12.1 | 55.5 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 152 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 23 Participants | 16 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 40 Participants | 122 Participants | 82 Participants |
| Sex: Female, Male Female | 6 Participants | 18 Participants | 12 Participants |
| Sex: Female, Male Male | 47 Participants | 141 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 106 | 8 / 53 |
| other Total, other adverse events | 33 / 106 | 12 / 53 |
| serious Total, serious adverse events | 88 / 106 | 41 / 53 |
Outcome results
Primary
Number of Participants With Adverse Events
Safety as assessed by number of study intervention-related adverse events
Time frame: up to 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MPC Intramyocardial Injection | Number of Participants With Adverse Events | Serious AE | 88 Participants |
| MPC Intramyocardial Injection | Number of Participants With Adverse Events | Other than Serious AE | 33 Participants |
| Control Solution | Number of Participants With Adverse Events | Serious AE | 44 Participants |
| Control Solution | Number of Participants With Adverse Events | Other than Serious AE | 12 Participants |
Primary
Number of Temporary Weans From LVAD Support Tolerated
functional status, defined by the number of temporary weans from LVAD support tolerated over the 6 months post-randomization. A successful wean is the ability to tolerate temporary weaning from LVAD support for 30 minutes without sustained symptoms of worsening heart failure. Wean failures are defined as inability to tolerate the temporary wean for 30 minutes; death; or patient too unstable, in the judgment of the primary heart failure cardiologist, to tolerate the wean attempt.
Time frame: up to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MPC Intramyocardial Injection | Number of Temporary Weans From LVAD Support Tolerated | 0.61 number of weans | Standard Deviation 0.41 |
| Control Solution | Number of Temporary Weans From LVAD Support Tolerated | 0.58 number of weans | Standard Deviation 0.45 |
Secondary
Change in Quality of Life (QoL)
Quality of life will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), a widely used tool in heart failure populations, and the Short Form 12 (SF12), a widely used overall health status measure.
Time frame: 6 months and 12 months
Secondary
Controlled Oral Word Association
Cognitive performance will be assessed using the Controlled Oral Word Association. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months
Secondary
Digit Span
Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months
Secondary
Digit Symbol Substitution Test
Cognitive performance will be assessed using the Digit Symbol Substitution Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months
Secondary
Functional Status
functional status, defined by the number of temporary weans from LVAD support tolerated
Time frame: up to 12 months
Secondary
Histopathological Assessments of Myocardial Tissue
Time frame: up to 12 months
Secondary
Hopkins Verbal Learning Test
Cognitive performance will be assessed Hopkins Verbal Learning Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months
Secondary
Hospital Costs
Hospital resource use
Time frame: up to 12 months
Secondary
Hospitalizations
Frequency and cause of readmissions
Time frame: up to 12 months
Secondary
Length of Stay
Length of stay of index hospitalization
Time frame: up to 12 months
Secondary
MCG Complex Figures
Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months
Secondary
Overall Survival
Time frame: up to 12 months
Secondary
Physiologic Assessments
Echocardiographic assessments of the myocardial size and function by transthoracic echocardiography with LVAD at full support, and as tolerated following 6-Minute Walk Test (MWT) while weaned from LVAD support (for patients who tolerate wean from LVAD support for 30 minutes)
Time frame: up to 12 months
Secondary
Trailmaking Tests A and B
Cognitive performance will be assessed using Trailmaking Tests A and B. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time frame: 3 months and 12 months