Cell Therapy in HFpEF

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to investigate safety and efficacy of transendocardial CD34+ cell therapy in patients with HFpEF by evaluating changes in myocardial structure and function, patient exercise capacity and clinical outcome. The safety end-points include serious adverse events (SAEs), defined as any serious event that may result in persistent or significant disability or incapacity and included death, heart transplantation, sustained ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), and heart failure exacerbation requiring hospitalization.

Detailed Description
-----------------
In all patients, peripheral blood stem cells will be mobilized by daily subcutaneous injections of G-CSF (10 mcg/kg, divided b.i.d) for 5 days. Peripheral blood stem cells will then be collected with Miltenyi cell separator (Miltenyi Biotech, Germany) and the magnetic cell separator Isolex 300i (Nexell Therapeutics Inc., California, USA) will be used for the immunomagnetic positive selection of the CD34+ cells.

Official Title
-----------------
A PILOT TRIAL OF CELL THERAPY IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

Conditions
-----------------
Heart Failure With Normal Ejection Fraction

Intervention / Treatment
-----------------
* Biological: Cell Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Preserved left ventricular systolic function on echocardiography (LVEF>50%) Evidence of diastolic dysfunction by echocardiography (E/e'>15) Symptoms of heart failure NT-proBNP levels >300 pg/ml absence of permanent atrial fibrillation Exclusion Criteria: acute multi-organ failure history of any malignant disease within 5 years diminished functional capacity due to non-cardiac co-morbidities (COPD, PAOD, morbid obesity) pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: The study is designed in a prospective crossover fashion. In Phase 1 of the study, all patients are treated with optimization of medical therapy for 6 months. Thereafter, all patients cross over to Phase 2 of the study, where they receive transendocardial CD34+ cell therapy. Follow-up of Phase 2 lasts for 6 months. At the time of enrollment (6 months before cell therapy), at time of cell therapy, and 6 months thereafter we will perform detailed clinical evaluation, laboratory assays, echocardiography, 6-minute walk test, and measure plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SC Group<br>In Phase 1 of the study, all patients will be treated with optimization of medical therapy for 6 months. Thereafter, all patients will cros over to Phase 2 of the study, where they will receive transendocardial CD34+ cell therapy. Follow-up of Phase 2 will last for 6 months. At the time of enrollment (6 months before cell therapy), at time of cell therapy, and 6 months thereafter we will perform detailed clinical evaluation, laboratory assays, echocardiography, 6-minute walk test, and measure plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP). | Biological: Cell Therapy<br>* Electro-anatomical mapping will be performed using the Biosense NOGA system (Biosense-Webster, Diamond Bar, California). Local diastolic function will be assessed by a novel algorhithm that allows for the measuring local ventricular relaxation times at each of the sampling points. Target areas for cell delivery will be defined as the myocardial segments with the evidence of local diastolic dysfunction and myocardial hibernation. Transendocardial delivery of cell suspension in the SC Group will be performed with MyoStar® (Biosense Webster) injection catheter. Each patient will receive 20 injections of 0.3 mL of stem cell suspension.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular filling pressures (E/e') assessed by echocardiography | The E/e' ratio will be calculated from early transmitral velocity divided by peak left ventricular relaxation velocity for estimation of the left ventricular filling pressure. | Baseline, 6 months and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in exercise capacity | 6-minute walk test will be performed by a blinded observer according to the standard protocol. | Baseline, 6 months and 1 year | 
| Change in NT-proBNP levels | NT-proBNP assays will be performed at a central independent laboratory, blinded to the patient's clinical data using a commercially available kit (Roche Diagnostics, Mannheim, Germany). | Baseline, 6 months and 1 year | 
| Change in systolic strain | Left ventricular longitudinal strains will be analyzed by speckle tracking echocardiography from apical four-chamber, two-chamber, and long-axis views. | Baseline, 6 months and 1 year | 
| Change in diastolic dysfunction grade | Diastolic dysfunction will be graded according based on E/A ratio and left atrial pressure estimation. | Baseline, 6 months and 1 year |