Cell Therapy and Myocardial Recovery in Heart Failure Patients Undergoing Left Ventricular Assist Device Support

Study Overview
=================
Brief Summary
-----------------
The goal of CELL-VAD Pilot trial is to investigate a personalized stem cell therapy approach for patients with advanced non-ischemic chronic heart failure (NICM) who are supported by LVAD. In the clinical trial, the investigators aim to enroll 10 patients with NICM, scheduled for LVAD implantation. After successful LVAD implantation, patients will be enrolled and followed for 2 months to allow for postoperative rehabilitation and heart failure medical therapy and LVAD support optimization. All patients will then undergo autologous CD34+ cell therapy which will be intracoronaryly delivered to the target myocardium using NOGA electromechanical mapping system. All patients will be followed for 6 months after cell therapy. At baseline, and at 1, 3, and 6 months after cell therapy, the investigators will perform comprehensive clinical evaluation.

Detailed Description
-----------------
PROBLEM IDENTIFICATION Left ventricular assist device (LVAD) technology has evolved significantly and represents a standard of care for patients with advanced chronic heart failure. However, a significant discrepancy exists between structural and functional recovery of the failing myocardium, as only a small fraction (2%) of LVAD-supported patients demonstrate reverse structural remodeling and eventually reach clinically significant and stable functional improvement that allows for LVAD removal. Thus, there is a significant unmet need to define better the mechanisms of myocardial reverse remodeling in advanced chronic heart failure patients undergoing LVAD support. OBJECTIVES The goal of CELL-VAD Pilot trial is to investigate a personalized stem cell therapy approach for patients with advanced non-ischemic chronic heart failure (NICM) who are supported by LVAD. The investigators propose a Phase II non-randomized single-center clinical study focusing on (1) the administration of stem cell therapy that would allow for durable improvements in heart function and structure in NICM-LVAD patients. By using integrated analysis of multimodality imaging and biomarkers of fibrosis and angiogenesis, this project aims to (2) better define the pathophysiological mechanisms involved in myocardial recovery. Additionally, the investigators also aim to (3) define the safety parameters of stem cell therapy in NICM-LVAD patients. Based on these aims, the specific objectives of the CELL-VAD Pilot trial are: The primary objective of this study is to investigate the safety and efficacy of stem cell therapy in NICM-LVAD patients, by evaluating changes in left ventricular structure and function, biomarkers of neurohormonal activation, patient exercise capacity, and clinical outcome. The secondary objective of this study is to better define pathophysiological mechanisms involved in myocardial recovery in NICM-LVAD patients, by evaluating temporal changes in myocardial perfusion and in biomarkers of myocardial fibrosis in angiogenesis. STUDY DESIGN The CELL-VAD Pilot trial consists of a clinical trial (WP1) and a multimodality imaging platform (WP2). The overall duration of the project is 3 years (36 months). In the clinical trial, the investigators aim to enroll 10 patients with NICM, scheduled for LVAD implantation. After successful LVAD implantation, patients will be enrolled and followed for 2 months to allow for postoperative rehabilitation and heart failure medical therapy and LVAD support optimization. All patients will then undergo autologous CD34+ cell therapy which will be delivered via the intracoronary route. All patients will be followed for 6 months after cell therapy. At baseline, and at 1, 3, and 6 months after cell therapy, the investigators will perform comprehensive clinical evaluation. Clinical, biochemical, biomarker-related, imaging, and myocardial histology data will be transferred to a secured central database. The investigators also aim to develop a personalized multimodality imaging platform by integrating the data obtained from advanced echocardiography and PET imaging. EXPECTED OUTCOMES The investigators expect to demonstrate that in NICM-LVAD patients transendocardial autologous CD34+ cell therapy is safe and efficient, promoting the structural and functional reverse remodelling of the failing myocardium. Additionally, the results of this trial will establish a solid framework of knowledge and expertise for future clinical trials to build on.

Official Title
-----------------
The Effects of Cell Therapy on Myocardial Recovery in Chronic Heart Failure Patients Undergoing Left Ventricular Assist Device Support: A Pilot Trial (CELL-VAD Pilot)

Conditions
-----------------
Heart Failure, Mechanical Circulatory Support

Intervention / Treatment
-----------------
* Biological: CD34+ stem cell therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Patient inclusion criteria will consist of all of the following: non-ischemic dilated cardiomyopathy patient accepted for LVAD support optimal (or maximal tolerable therapy) heart failure ≥ 2 months age 18-65 years ability to provide informed consent Patient exclusion criteria will consist of any of the following: ischemic cardiomyopathy Cardiomyopathy with a reversible cause that has not been treated e.g. thyroid disease, alcohol abuse, hypophosphataemia, hypocalcaemia, cocaine abuse, selenium toxicity & chronic uncontrolled tachycardia. Cardiomyopathy in association with a neuromuscular disorder e.g. Duchenne's progressive muscular dystrophy. ongoing or recent (less than 1 month) infection acute multi-organ failure clinically significant anemia (Hb < 10 g/dL) clinically significant leukopenia (L < 2 x 109/L) or leukocytosis (L > 14 x 109/L) clinically significant thrombocytopenia (TRC < 50 x 109/L) known disorders of hemostasis that can not be corrected history of any thromboembolic complications chronic kidney disease (higher than stage III) chronic liver disease (Child B or C) diminished functional capacity for other reasons such as COPD, moderate or severe claudications, severe musculosceletal system pain or morbid obesity (BMI > 35 kg/m2) aortic stenosis (AVA < 1.3 cm2) or ocluded aortic valve artificial (mechanical or biological) aortic valve patients with reduced immune response history of limphoprolipherative disorders or malignancy within 5 years left ventricular thrombus participation in another interventional clinical trial life expectancy less than 12 months known hypersensitivity to DMSO, penicillin or streptomycin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>After successful LVAD implantation, patients will be enrolled and followed for 2 months to allow for postoperative rehabilitation and heart failure medical therapy and LVAD support optimization. All patients will then undergo autologous CD34+ cell therapy which will be delivered via intracoronary route. All patients will be followed for 6 months after cell therapy. At baseline, and at 1, 3 and 6 months after cell therapy, we will perform comprehensive clinical evaluation. Clinical, biochemical, biomarker-related, imaging and myocardial histology data will be transferred to a secured central database. | Biological: CD34+ stem cell therapy<br>* After 5-days GCSF stimulation all patients will undergo apheresis to obtain CD34+ cell which will subsequently be injected in the target coronary artery using microcatheter.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in left ventricular ejection fraction (LVEF) | change in left ventricular ejection fraction (LVEF), measured by transthoracic echocardiography using Simpson's rule between the time of stem cell therapy and 6 months. | Baseline to 6 months | 
| Changes in left ventricular end-systolic and end-diastolic dimensions | Changes in left ventricular end-systolic (LVESd) and end-diastolic dimensions (LVEDd) measured by transthoracic echocardiography in parasternal longitudinal axis with expected change > 10%. | Baseline to 3 and 6 months | 
| Changes in left ventricular longitudinal and circumferential strains | Changes in left ventricular longitudinal and circumferential strains will be measured using transthoracic echocardiography and segmental wall motion analysis with expected change > 10%. | Baseline to 3 and 6 months | 
| Changes in right ventricular size | Changes in right ventricular size (RVIDd) will be measured using transthoracic echocardiography with expected change > 10%. | Baseline to 3 and 6 months | 
| Change in serum neurohumoral activation | Change in serum neurohumoral activation will be assessed measuring NT-proBNP serum levels, with expected decrease > 30%. | Baseline to 3 and 6 months | 
| Changes in serum markers of fibrosis and angiogenesis | Changes in serum markers of fibrosis and angiogenesis will be assessed by measuring biomarkers of fibrosis and angiogenesis using Luminex commercially available kits (Human XL Cytokine Luminex® Performance Assay 46-plex); any detectable change will be considered a positive response. | Baseline to 3 and 6 months | 
| Change in 6-minute walk test | Change in 6-minute walk test with expected increase > 30 m | Baseline to 3 and 6 months | 
| Change in quality of life questionnaire score | Change in quality of life KCCQ questionnaire score with expected decrease of ≥ 5 points | Baseline to 3 and 6 months | 
| Change in heart failure-related hospitalization | Change in heart failure-related hospitalization; any decrease will be considered | Baseline to 3 and 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
heart failure, mechanical circulatory support, stem cells