Heart Failure
Conditions
Keywords
Heart failure, Left ventricular assist device, Stem cells
Brief summary
The purpose of this study is to determine if the delivery of cells just after implantation of left ventricular assist device will help to improve the pumping function of your heart and minimize heart enlargement in the future. The cells will be obtained by aspiration or withdrawal of fluid from your bone marrow from your pelvic bone using a needle and syringe. This would not take place until 24-48 hours prior to your planned left ventricular assist device implantation. During the surgery the surgeons will inject the prepared cells that were taken from your bone marrow and inject it into your heart muscle. This study will test whether receiving your own bone marrow cells directly into your heart will help your heart to recover function after placement of a left ventricular assist device.
Detailed description
Patients who meet the inclusion and exclusion criteria and agree to participate will be enrolled in the study. All the patients will have a baseline EKG, Laboratory tests, 2D ECHO and PET/CT imaging.Day prior to the LVAD implantation all the patients will undergo bone marrow aspiration. Bone marrow aspirate will be processed according to the protocols used by that facility. After processing, the bone marrow mononuclear cells will then be suspended in 2ml of 5% human serum albumin and labeled per the standard protocol of the facility. Patients will be randomized in a 2:1 fashion either to receive cells or 5% serum albumin. Under general anesthesia using the standard techniques the HeartMate II (LVAD) will be placed. The LVAD will be inserted into the LV apex (with removal of 2 x 2 cm ventricular core). The tissue core will be processed for RNA isolation and morphological analysis. CV surgeon will inject either the cells or placebo directly in to the myocardium in the LAD territory. Ten separate injections will be delivered into the LV free wall (20 X 106 cells / 400 micro lit). The injection sites will be marked with Titanium surgical clips. Subjects will be managed at all times by the current standard of care in this hospital for the patients with an LVAD. Routine postoperative care procedures will be followed with close follow-up for dysrrhythmias or signs of infection. Tissue sample from the core of the left ventricular apex removed at the time of implantation of LVAD will be compared with the myocardium (marked with the surgical clips) from the explanted heart at the time of transplantation. These samples from the experimental subjects and control hearts will be examined for morphology for interstitial fibrosis, hypertrophy, myocyte diameter and myocytolysis as well as for gene expression using RT-PCR. Research-related follow-up will take place at weeks 2, 4, 6, 8 and months 6, 12, 18 and 24 after LVAD implant at the Clinical Trial Center of the Cardiology Division at the University of Minnesota. Patients will be examined by the PI or Sub-I at each visit. Follow up data to be obtained at these clinic visits is outlined in the protocol
Interventions
BIOLOGICALIntramyocardial Delivery of Bone Marrow Derived Mononuclear Cells
Ten separate injections will be delivered into the LV free wall (20 X 106 cells / 400 micro lit).
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Severe LV dysfunction with EF \< 30% with cardiomyopathy ( Ischemic and non ischemic) 2. NYHA Class III and IV 3. No revascularization options available 4. LVAD placement as destination therapy or bridging to transplantation 5. Age between 18-80 years
Exclusion criteria
1. History of recent malignancy( less than one year) . 2. Unstable hemodynamics at the time of the implant; defined by need for increasing vasopressor medication in the last 24 hours or blood pressure \< 70 systolic, or cardiac index \< 1.3 liters/min. 3. Coronary anatomy suitable for revascularization at the time of surgery 4. Pregnancy confirmed by positive urine test 5. Lactating mothers 6. Renal failure with serum creatinine \>3.0, or are receiving chronic dialysis support. 7. Inability to undergo PET/CT imaging. 8. A history of any significant recent bleeding disorder or coagulation profile of concern for acute bleeding, such as INR \>2.0 (not on anticoagulant), platelet count \<100,000, or hemoglobin \<8.0 gr/dl. 9. Patients with known infectious disease (Hepatitis, HIV) etc. 10. Patients with three times or more of the upper limits of normal enzymes. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Cell Delivery | 24 months | Safety as measured by the total number of adverse events per group. |
| Improvement in Myocardial Viability by PET/CT Scan | baseline, 10 weeks | Change in LAD segments from baseline to 10 weeks. PET scan viability is reported by segment on a scale of 0-4. A score of 0, 1, or 2 are categorized as viable/healthy heart tissue and a score of 3 or 4 are categorized as not viable/scar tissue. No change or better in viability will be reported to determine safety of cell injection. Measurement is reported as number of segment that remained the same or improved were considered safe for stem cell injection. |
| Combined End Points of Death | 24 months | Number of participants who expired during the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Turned Down Without Meeting LVAD Stopping Rules | 10 weeks | LVAD turn-down was completed at 10 weeks. Hemodynamic measurements were taken and reported with nominal LVAD support and then again at peak exercise. LVAD turn-down protocol was followed to ensure safety of patient while turning down their LVAD support. After each turn-down we waited 10 minutes and repeated ECHO, RHC, LVAD parameters, vital signs. Stopping parameters for turn down: 1. Significant symptoms (clinician judgement, although low threshold to stop test) 2. CVP\>20 or increase by more than 10 (e.g., 5 to 16) 3. PCWP\>25 or increase by more than 10 (e.g., 11 to 22) 4. Hypotension 5. Increase in LVIDd by \>1.5 cm 6. Aortic valve opening minimally (less than 1 in 5 beats, e.g.) The number of patients that could be turn-down without meeting stopping rules and were able to exercise were reported per group. |
| Change in Left Ventricular Dimensions | 10 weeks | Change in left ventricular dimensions assessed by ECHO at baseline compared to 10 weeks with LVAD turn-down to 6000 RPMs. |
| Histological Assessment | 24 months | Data collection was insufficient for data analysis. Samples were collected but no histological analysis performed. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stem Cell Therapy Intramyocardial Delivery of Bone Marrow Derived Mononuclear Cells in Patients with Severe LV Dysfunction and LVAD Support
Intramyocardial Delivery of Bone Marrow Derived Mononuclear Cells: Ten separate injections will be delivered into the LV free wall (20 X 106 cells / 400 micro lit). | 16 |
| Placebo Intramyocardial Delivery Placebo solution into Patients with Severe LV Dysfunction and LVAD Support
Intramyocardial Delivery of Bone Marrow Derived Mononuclear Cells: Ten separate injections will be delivered into the LV free wall (20 X 106 cells / 400 micro lit). | 9 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Stem Cell Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 8 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 8 Participants | 12 Participants |
| Age, Continuous | 65.1 years STANDARD_DEVIATION 8.6 | 62.3 years STANDARD_DEVIATION 8.68 | 63.3 years STANDARD_DEVIATION 8.58 |
| Region of Enrollment United States | 9 participants | 16 participants | 25 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 16 | 3 / 9 |
| other Total, other adverse events | 0 / 16 | 0 / 9 |
| serious Total, serious adverse events | 13 / 16 | 7 / 9 |
Outcome results
Primary
Combined End Points of Death
Number of participants who expired during the study.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stem Cell Therapy | Combined End Points of Death | 2 Participants |
| Placebo | Combined End Points of Death | 3 Participants |
Primary
Improvement in Myocardial Viability by PET/CT Scan
Change in LAD segments from baseline to 10 weeks. PET scan viability is reported by segment on a scale of 0-4. A score of 0, 1, or 2 are categorized as viable/healthy heart tissue and a score of 3 or 4 are categorized as not viable/scar tissue. No change or better in viability will be reported to determine safety of cell injection. Measurement is reported as number of segment that remained the same or improved were considered safe for stem cell injection.
Time frame: baseline, 10 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stem Cell Therapy | Improvement in Myocardial Viability by PET/CT Scan | Anterior wall base segment | 14 safe segments |
| Stem Cell Therapy | Improvement in Myocardial Viability by PET/CT Scan | Anterior wall mid segment | 14 safe segments |
| Stem Cell Therapy | Improvement in Myocardial Viability by PET/CT Scan | Anterior lateral wall base segment | 15 safe segments |
| Stem Cell Therapy | Improvement in Myocardial Viability by PET/CT Scan | Anterior lateral wall mid segment | 15 safe segments |
| Placebo | Improvement in Myocardial Viability by PET/CT Scan | Anterior lateral wall mid segment | 4 safe segments |
| Placebo | Improvement in Myocardial Viability by PET/CT Scan | Anterior wall base segment | 4 safe segments |
| Placebo | Improvement in Myocardial Viability by PET/CT Scan | Anterior lateral wall base segment | 4 safe segments |
| Placebo | Improvement in Myocardial Viability by PET/CT Scan | Anterior wall mid segment | 4 safe segments |
Primary
Safety of Cell Delivery
Safety as measured by the total number of adverse events per group.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stem Cell Therapy | Safety of Cell Delivery | 1 adverse events |
| Placebo | Safety of Cell Delivery | 0 adverse events |
Secondary
Change in Left Ventricular Dimensions
Change in left ventricular dimensions assessed by ECHO at baseline compared to 10 weeks with LVAD turn-down to 6000 RPMs.
Time frame: 10 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stem Cell Therapy | Change in Left Ventricular Dimensions | Change from baseline to 10 weeks in LVESD | -0.73 cm | Standard Deviation 1.07 |
| Stem Cell Therapy | Change in Left Ventricular Dimensions | Change from baseline to 10 weeks in LVEDD | -0.49 cm | Standard Deviation 1.004 |
| Placebo | Change in Left Ventricular Dimensions | Change from baseline to 10 weeks in LVEDD | -0.57 cm | Standard Deviation 0.76 |
| Placebo | Change in Left Ventricular Dimensions | Change from baseline to 10 weeks in LVESD | -0.62 cm | Standard Deviation 0.89 |
Secondary
Histological Assessment
Data collection was insufficient for data analysis. Samples were collected but no histological analysis performed.
Time frame: 24 months
Population: Data collection was insufficient for data analysis. Samples were collected but no histological analysis performed.
Secondary
Number of Participants Turned Down Without Meeting LVAD Stopping Rules
LVAD turn-down was completed at 10 weeks. Hemodynamic measurements were taken and reported with nominal LVAD support and then again at peak exercise. LVAD turn-down protocol was followed to ensure safety of patient while turning down their LVAD support. After each turn-down we waited 10 minutes and repeated ECHO, RHC, LVAD parameters, vital signs. Stopping parameters for turn down: 1. Significant symptoms (clinician judgement, although low threshold to stop test) 2. CVP\>20 or increase by more than 10 (e.g., 5 to 16) 3. PCWP\>25 or increase by more than 10 (e.g., 11 to 22) 4. Hypotension 5. Increase in LVIDd by \>1.5 cm 6. Aortic valve opening minimally (less than 1 in 5 beats, e.g.) The number of patients that could be turn-down without meeting stopping rules and were able to exercise were reported per group.
Time frame: 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stem Cell Therapy | Number of Participants Turned Down Without Meeting LVAD Stopping Rules | 12 Participants |
| Placebo | Number of Participants Turned Down Without Meeting LVAD Stopping Rules | 2 Participants |