Serial Infusions of Allogeneic Mesenchymal Stem Cells in Cardiomyopathy Patients With Left Ventricular Assist Device

Study Overview
=================
Brief Summary
-----------------
A study to assess the safety and preliminary efficacy of serial intravenous dose of Allogeneic Mesenchymal Bone Marrow Cells in subjects with heart failure and implanted left ventricular assist devices.

Detailed Description
-----------------
A double-blind, placebo-controlled, single-center, randomized study to assess the safety and preliminary efficacy of a three serial intravenous doses of allogeneic mesenchymal bone marrow cells to subjects with heart failure and implanted left ventricular assist devices.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Phase IIa Study of the Safety and Efficacy of Intravenous Delivery of Allogeneic Mesenchymal Stem Cells in Cardiomyopathy Patients and Implanted Left Ventricular Assist Device

Conditions
-----------------
Ischemic Heart Disease, Non-ischemic Cardiomyopathy

Intervention / Treatment
-----------------
* Biological: Human Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years. Advanced Heart Failure Advanced HF defined as HF requiring LVAD implantation and deemed stable on his/her LVAD. On stable medical therapy (per the discretion of the treating physician) including beta-blockers, ACE-inhibitors, angiotensin receptors blockers, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, isosorbide, hydralazine, and mineralocorticoid receptor antagonists) and optimized pump speed for at least a month prior to randomization. HS-CRP level≥2 mg/l. NYHA class II-III symptoms. Ability to understand and provide signed informed consent. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled safety follow-up visits Exclusion Criteria: Women of childbearing potential. Postmenopausal women or women with permanent contraception method (defined as total hysterectomy) will not be excluded. History of debilitating stroke (modified Rankin Score > 3) within 3 months. The likelihood of requirement of cardiac surgery during the study period. Presence of clinically significant, uncorrected left sided valvular heart disease, active acute myocarditis, or uncontrolled hypertension defined as Persistently elevated mean arterial blood pressure (>100 mmHg). Echocardiography within 12 months of screening. Patients can be re-evaluated, at the discretion of the investigator. QTc >550 ms (in the absence of bundle branch block, interventricular conduction delay or ventricular pacing). Electrocardiogram (ECG) within 60 days. History of cardiac arrest within 3 months. Hypertrophic or infiltrative cardiomyopathy. Considered or listed for organ transplantation or history of organ transplantation Illness other than HF with life expectancy less than 12 months. Enrolled in an interventional trial or received an experimental drug or device within 30 days of randomization. Left ventricular assist device implantation >2 years prior to enrollment. Biventricular assist device (Bi-VAD) support. Severe COPD defined by FEV1<1L, FEV1/FVC<70% within 12 months if known history of COPD, otherwise FEV1<1L, FEV1/FVC<70% within 24 months Uncontrolled seizure disorder. Clinically significant hematologic, hepatic, or renal impairment as determined by screening clinical laboratory tests within the last 30 days: Liver disease = ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal Renal disease = on long term dialysis Hematologic = Unexplained persistent leukocytosis (WBC >11 K/UL) or hemoglobin < 8.5 gm/dl Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory abnormality, that in the judgment of the investigator or sponsor may affect compliance with the study protocol or pose a safety risk to the subject. Inability to comply with the conditions of the protocol. Acute coronary syndrome within 4 weeks (clinical diagnosis, confirmed by electrocardiographic abnormalities and elevation of troponin-I). Malignancy within the previous five years, except adequately treated basal cell carcinoma, provided that it is neither infiltrating nor sclerosing, and carcinoma in situ of the cervix. Active uncontrolled systemic infection. Positive blood or deep tissue cultures or clinical or imaging evidence of systemic infection despite complete course of effective antimicrobial therapy as determined by infectious diseases. Localized (non-systemic) infection is not an exclusion criterion. Patients can be re-evaluated, at the discretion of the investigator. Early postpartum cardiomyopathy (within six months of diagnosis). Presence of inherited or acquired immune deficiency or human immunodeficiency virus infection (HIV). Negative HIV test within the preceding 12 months is required. Systemic corticosteroids, immunosuppressive drug therapy (cyclophosphamide, methotrexate, cyclosporine, tacrolimus, azathioprine, mycophenolate, sirolimus, etc.), and DNA depleting or cytotoxic drugs taken within four weeks prior to study treatment. Known Porphyria. Allergy to sodium citrate or any caine type of local anesthetic. Patient enrolled in hospice care.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)<br>Three intravenous infusions of 1.5 million (aMBMC) per kg administered at approximately 2mL/min. Maximum dose as for 100kg subject or 150 million cells for any subject 100kg or more with each infusion 1 month apart. | Biological: Human Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)<br>* Allogeneic Mesenchymal Bone Marrow Cells (aMBMC) 1.5 million cells/kg<br>|
| Placebo Comparator: Placebo<br>Three intravenous infusions of 1.5 mL/kg Lactated Ringer's Solution with each infusion 1 month apart. | Other: Placebo<br>* 1.5 mL/kg Lactated Ringer's Solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Temperature | Temperature | up to 12 months post enrollment | 
| Uncontrolled Systemic Infection | Number of admission for uncontrolled systemic infection | up to 12 months post enrollment | 
| All-cause Mortality | Rate of Death | up to 12 months post enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NK Cell Depletion | percent reduction in NK cells | Baseline to day 90 | 
| Change in the Following Cardiac Biomarker | The change in the lab values N-Terminal Prohormone of Brain Natriuretic Peptide (NT-ProBNP) | Baseline and day 90 post initial infusion | 
| Change in RV Systolic Function | Change in RV systolic function | Baseline and day 90 post initial infusion | 
| Hospitalizations Due to Right Heart Failure | Number of hospitalizations for to right heart failure | day 90 | 
| 6 Minute Walk Distance Changes | 6 minute walk distance changes | Baseline and day 90 post initial infusion | 
| Gout Flares | Count of gout flares | Day 90 |