Randomized Clinical Trial to Evaluate the Regenerative Capacity of CardioCell in Patients With Chronic Ischaemic Heart Failure (CIHF)

Study Overview
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Brief Summary
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The main objective of the CIRCULATE project is to compare the clinical outcomes of CardioCell administration in treatment of ischemic damages of cardiovascular system with control group, who will receive the placebo.

Detailed Description
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The CIHF trial will enroll 105 patients with randomization into active and placebo therapy with 2:1 ratio. Additional 5-10 subjects meeting inclusion/exclusion criteria will receive, in a non-blinded fashion, labelled CardioCell to determine the early myocardial uptake and retention of IMP. The primary research question of this project is to check if the administration of CardioCell could improve the clinical outcomes in patients with CIHF. There are several secondary questions, defined by secondary endpoints in each cohort, e.g.: if the investigated treatment is possible to administered, if the investigated treatment and way of CardioCell administration is safe, if it is possible to define any selected subgroup in which the treatment results are significantly different than in whole group.

Official Title
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Regeneration of Ischemic Damages in Cardiovascular System Using Wharton's Jelly as an Unlimited Source of Mesenchymal Stem Cells for Regenerative Medicine. Project of the National Centre for Research and Development (Poland) 'STRATEGMED II'. Randomized Clinical Trial to Evaluate the Regenerative Capacity of CardioCell in Patients With Chronic Ischaemic Heart Failure (CIHF)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: CardioCell
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-80 years Diagnosis of ischemic heart failure (supported by history of CAD or revascularization by PCI or CABG procedure) without known need for revascularization or feasibility of revascularization Substantial chronic ischemic myocardial injury as demonstrated by LVEF ≤45% by SPECT and the clinical stage of NYHA II or III At least 50% viable myocardium (SPECT) Patency of at least two major coronary arteries and/or bypass grafts supplying their territories (confirmed in angiography within 12 months) Clinically stable CIHF for at least 3 months on guideline recommended therapy Signed informed consent Exclusion Criteria: Other than ischemic cause of cardiomyopathy Less than 3 months from any substantial therapeutic intervention (such as, e.g. CRT/ICD fitting or revascularization) Less than 3 months from ACS BMI lower than 18 or greater than 45kg/m2 Severe valvular heart disease or left ventricle aneurysm requiring aneurysmectomy or other structural interventions Candidate for heart transplantation Active or any history of malignancy or tumor Moderate or severe immunodeficiency Chronic immunosuppressive therapy Acute or chronic infection Coagulopathies Known alcohol or drug dependence Severe renal dysfunction (eGFR<20mL/min) Soft tissue disease or local infection in a place of required artery puncture Pregnancy or breastfeeding Females of childbearing potential who do not use a highly effective method of contraception Females of childbearing potential in absence of a negative highly sensitive urine or serum pregnancy test Participation in any other clinical research study that has not reached the primary efficacy endpoint or otherwise would interfere with the patient's participation in this project Life expectancy < 12 months Any objective or subjective reason for inability to attend follow-up visits Any concurrent disease or condition that, in the opinion of the investigator, would make the patient unsuitable for participation in the project

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The CIHF trial will enroll 105 patients with randomization into active and placebo therapy with 2:1 ratio. Additional 5-10 subjects meeting inclusion/exclusion criteria will receive, in a non-blinded fashion, labelled CardioCell to determine the early myocardial uptake and retention of IMP.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Group<br>Patients randomized to the active treatment group: Transcoronary or trans-bypass graft administration of CardioCell consist 30 000 000 cells (suspended in 20 ml of 0.9% NaCl and 5% albumin) will be performed using a dedicated cell delivery catheter. The cell delivery catheter is a typical coronary balloon catheter that is CE marked (1.2x10 mm balloon, RX system) modified to include cell delivery perforations in the balloon section of the catheter. The cell delivery catheter has been demonstrated not to affect cell viability or other cell properties. | Drug: CardioCell<br>* Patients randomized to the active treatment group will receive transcoronary or trans-bypass graft administration of 30 000 000 cells (suspended in 20 ml of 0.9% NaCl and 5% albumin). Injection will be performed using a dedicated cell delivery catheter. The cell delivery catheter is a typical coronary balloon catheter that is CE marked (1.2x10 mm balloon, RX system) modified to include cell delivery perforations in the balloon section of the catheter. The cell delivery catheter has been demonstrated not to affect cell viability or other cell properties.<br>* Other names: CardioCell administration;|
| Placebo Comparator: Control Group<br>Patients randomized to the placebo group will receive Placebos consist 0.9% NaCl and 5% albumin injections (in the same volumes as CardioCell) via the coronary arter(ies)/bypass grafts. The CardioCell and placebo are distributed encoded, in an indistinguishable form. | Drug: Placebos<br>* Patients randomized to the placebo group will receive Placebos consist 0.9% NaCl and 5% albumin injections (in the same volumes as CardioCell) via the coronary arter(ies)/bypass grafts. The CardioCell and placebo are distributed encoded, in an indistinguishable form.<br>* Other names: Placebo administration;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricle ejection fraction (LVEF) increase | Left ventricle ejection fraction (LVEF) increase, assessed by SPECT at 6M FU vs. during index (baseline) imaging - comparison between two groups (active vs placebo therapy). | 6 months FU | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| An increase the result of 6 minute walk test | An increase the result of 6 minute walk test at 3 and 6 month. | 3 and 6 month FU | 
| Myocardial perfusion improvement | Myocardial perfusion improvement assessed in SPECT at 6 month FU. | 6 month FU | 
| Myocardial perfusion improvement | Myocardial perfusion improvement assessed in cardiac MRI at 6 month FU. | 6 month FU | 
| An improvement the result of spiroergometric test | An improvement the result of spiroergometric test at 6 month FU. | 6 month FU | 
| Left ventricle ejection fraction (LVEF) change against baseline | Left ventricle ejection fraction (LVEF) change (in %) against baseline, assessed in echocardiography. | 6 month FU | 
| Left ventricle end-systolic volume (ESV) change against baseline | Left ventricle end-systolic volume (ESV, in ml) change against baseline, assessed in echocardiography. | 6 month FU | 
| Left ventricle end-diastolic volume (EDV) change against baseline | Left ventricle end-diastolic volume (EDV, in ml) change against baseline, assessed in echocardiography. | 6 month FU | 
| NT pro-BNP level | NT pro-BNP level at 3, 6 and 12 months in comparison to the baseline level. | 3, 6 and 12 months FU | 
| The occurrence of major adverse cardiovascular events | The occurrence of major adverse cardiovascular events (MACE including death, myocardial infarction, and hospitalization for heart failure) at 6 month and 1 year FU. | 6 month and 1 year FU | 
| Quality of life improvement | Quality of life improvement, assessed by SF-36 questionnaire or other dedicated for investigated population at 6 month and 1 year FU. | 6 month and 1 year FU |