Cell Therapy and Myocardial Recovery in Heart Failure Patients Undergoing Left Ventricular Assist Device Support (CELL-VAD)

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Mechanical Circulatory Support
• Intervention / Treatment: Biological: CD34+ stem cell therapy

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gregor Poglajen, MD, PhD; Phone Number: +38615228671; Email: gregor.poglajen@kclj.si
• Study Contact Backup: Name: Mateja Lani; Phone Number: +38615221163; Email: mateja.lani@kclj.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • University Medical Center Ljubljana
    • Contact: Gregor Poglajen, MD, PhD; Phone Number: +38615228671; Email: gregor.poglajen@kclj.si
    • Contact: Bojan Vrtovec, MD, PhD; Phone Number: +38615221163; Email: bojan.vrtovec@kclj.si

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Patient inclusion criteria will consist of all of the following:

1. non-ischemic dilated cardiomyopathy
2. patient accepted for LVAD support
3. optimal (or maximal tolerable therapy) heart failure ≥ 2 months
4. age 18-65 years
5. ability to provide informed consent

Patient exclusion criteria will consist of any of the following:

1. ischemic cardiomyopathy
2. 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.
3. Cardiomyopathy in association with a neuromuscular disorder e.g. Duchenne's progressive muscular dystrophy.
4. ongoing or recent (less than 1 month) infection
5. acute multi-organ failure
6. clinically significant anemia (Hb < 10 g/dL)
7. clinically significant leukopenia (L < 2 x 109/L) or leukocytosis (L > 14 x 109/L)
8. clinically significant thrombocytopenia (TRC < 50 x 109/L)
9. known disorders of hemostasis that can not be corrected
10. history of any thromboembolic complications
11. chronic kidney disease (higher than stage III)
12. chronic liver disease (Child B or C)
13. diminished functional capacity for other reasons such as COPD, moderate or severe claudications, severe musculosceletal system pain or morbid obesity (BMI > 35 kg/m2)
14. aortic stenosis (AVA < 1.3 cm2) or ocluded aortic valve
15. artificial (mechanical or biological) aortic valve
16. patients with reduced immune response
17. history of limphoprolipherative disorders or malignancy within 5 years
18. left ventricular thrombus
19. participation in another interventional clinical trial
20. life expectancy less than 12 months
21. known hypersensitivity to DMSO, penicillin or streptomycin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment Arm; 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; 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.

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

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Principal Investigator: Bojan Vrtovec, MD, PhD, UMC Ljubljana

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: November 6, 2023
• First Submitted That Met QC Criteria: November 22, 2023
• First Posted (Actual): December 1, 2023

Study Record Updates

• Last Update Posted (Actual): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 22, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: stem cells; heart failure; mechanical circulatory support
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: UMC 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No