Repetitive Intramyocardial CD34+ Cell Therapy in Dilated Cardiomyopathy (REMEDIUM) (REMEDIUM)

Repetitive Intramyocardial CD34+ Cell Therapy in Dilated Cardiomyopathy

The goal of REMEDIUM project is to develop personalized stem cell therapy for patients with chronic heart failure due to dilated cardiomyopathy (DCM). The main focus of the project is (1) on repetitive administration of cell therapy that would allow for long-lasting improvements in heart function and outcome in this patient population. In parallel, the investigators aim to (2) develop a standardized patient-specific stem cell product that could be cryopreserved and stored in a stem cell bank for prolonged time periods, and used for therapeutic application when clinically indicated. By using a unique multimodality imaging platform, the goal of this project is also to (3) define standardized clinical criteria that would serve as a guideline for evaluation of the effects of stem cell therapy in future clinical trials and everyday clinical settings. Finally, to improve the clinical implementation of cell therapy,the investigators aim to (4) develop a stem cell delivery technique that could be used to treat both left and right and ventricular failure and could be implemented in a standardized fashion designed for a widespread clinical use.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Dilated Cardiomyopathy
• Intervention / Treatment: Biological: Stem cell therapy

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Slovenia
  • Please Select
    • Ljubljana, Please Select, Slovenia, 1000
      • UMC Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-70 years old
• Diagnosis of DCM according to European Society of Cardiology position statement
• Left ventricular ejection fraction (LVEF) by echocardiography 20-40%,
• New York Heart Association (NYHA) functional class heart failure II or III for at least 3 months before referral.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A; Repetitive stem cell administration	Biological: Stem cell therapy; Bone marrow cells will be mobilized into peripheral blood by daily subcutaneous injections of G-CSF (10 µg/kg daily) and collected by leukapheresis. Positive immunomagnetic selection of CD34+ cells will be performed. Electroanatomic mapping of the left ventricle will be performed using the Biosense NOGA system (Biosense-Webster®, Diamond Bar, CA). The target area for cell delivery will be defined as the myocardial segments with unipolar voltage potentials ≥8.3 mV, bipolar amplitudes >1.9 mV, and linear shortening <6%. Intramyocardial delivery of cell suspension will be performed with the MyoStar (BiosenseWebster®, Diamond Bar, CA) injection catheter. Each patient will receive 20 injections (0.3 mL each; total volume of 6 mL). All the procedures will be repeated 6 months after baseline.
Active Comparator: Group B; Single stem cell administration	Biological: Stem cell therapy; Bone marrow cells will be mobilized into peripheral blood by daily subcutaneous injections of G-CSF (10 µg/kg daily) and collected by leukapheresis. Positive immunomagnetic selection of CD34+ cells will be performed. Electroanatomic mapping of the left ventricle will be performed using the Biosense NOGA system (Biosense-Webster®, Diamond Bar, CA). The target area for cell delivery will be defined as the myocardial segments with unipolar voltage potentials ≥8.3 mV, bipolar amplitudes >1.9 mV, and linear shortening <6%. Intramyocardial delivery of cell suspension will be performed with the MyoStar (BiosenseWebster®, Diamond Bar, CA) injection catheter. Each patient will receive 20 injections (0.3 mL each; total volume of 6 mL). All the procedures will be repeated 6 months after baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular ejection fraction	The echocardiography data will be recorded and analyzed at the end of the study by an independent echocardiographer who will be blinded to the patient's treatment status and the timing of the recordings. Left ventricular end-systolic volume and end-diastolic volume and LVEF will be estimated using the Simpson's biplane method and left ventricular end-systolic dimension and end-diastolic dimension will be measured in the parasternal long axis view. All echocardiographic measurements will be averaged for 5 cycles.. The change in left ventricular ejection fraction (LVEF) between randomization and 1 year thereafter will be assessed by 2D echocardiography.	baseline and 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in regional wall motion	Left ventricular segmental wall motion analysis (strain) will be evaluated with TomTec software (TomTec Imaging Systems GmbH, Unterschleissheim, Germany), using a 17-segment model of the left ventricle.	baseline and 1 year
Change in left ventricular dimension	The change in left ventricular dimensions between randomization and 1 year thereafter will be assessed by 2D echocardiography.	1 year
Change in exercise capacity	Change in exercise capacity will be evaluated by 6-minute walk test was performed by a blinded observer according to the standard protocol.	baseline and 1 year
Change in NT-proBNP		baseline and 1 year

Other Outcome Measures

Outcome Measure	Time Frame
Incidence of ventricular arrhythmias	1 year
Cardiac mortality	1 year
Hospitalization for heart failure	1 year
Pump failure mortality	1 year

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana

Publications and helpful links

General Publications

• Vrtovec B, Poglajen G, Lezaic L, Sever M, Socan A, Domanovic D, Cernelc P, Torre-Amione G, Haddad F, Wu JC. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation. 2013 Sep 10;128(11 Suppl 1):S42-9. doi: 10.1161/CIRCULATIONAHA.112.000230.
• Vrtovec B, Poglajen G, Sever M, Zemljic G, Frljak S, Cerar A, Cukjati M, Jaklic M, Cernelc P, Haddad F, Wu JC. Effects of Repetitive Transendocardial CD34+ Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy. Circ Res. 2018 Jul 20;123(3):389-396. doi: 10.1161/CIRCRESAHA.117.312170. Epub 2018 Jun 7.
• Frljak S, Jaklic M, Zemljic G, Cerar A, Poglajen G, Vrtovec B. CD34+ Cell Transplantation Improves Right Ventricular Function in Patients with Nonischemic Dilated Cardiomyopathy. Stem Cells Transl Med. 2018 Feb;7(2):168-172. doi: 10.1002/sctm.17-0197.
• Rozman JZ, Perme MP, Jez M, Malicev E, Krasna M, Novakovic S, Vrtovec B, Rozman P. The effect of CD34+ cell telomere length and hTERT expression on the outcome of autologous CD34+ cell transplantation in patients with chronic heart failure. Mech Ageing Dev. 2017 Sep;166:42-47. doi: 10.1016/j.mad.2017.06.001. Epub 2017 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: September 16, 2014
• First Submitted That Met QC Criteria: September 24, 2014
• First Posted (Estimate): September 25, 2014

Study Record Updates

• Last Update Posted (Actual): January 23, 2018
• Last Update Submitted That Met QC Criteria: January 19, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: REMEDIUM