The goal of this clinical trial is to assess the safety and efficacy of three intravenous injections of the extracellulat vesicle-enriched secretome of cardiovascular progenitor cells in severely symptomatic patients with drug-refractory left ventricular (LV) dysfunction secondary to non-ischemic dilated cardiomyopathy. The main questions it aims to answer are:

• Are these repeated injections safe and well tolerated?
• Do they improve cardiac function and, if yes, to what extent?

The overall objective of this study is to assess the safety and efficacy of repeated intravenous injections of the secretome of cardiovascular progenitor cells in severely symptomatic patients with drug-refractory left ventricular (LV) dysfunction secondary to non-ischemic dilated cardiomyopathy.

The rationale and design of this trial are based on three main assumptions:

1. The tissue-repair capacity of transplanted cells can be duplicated by the delivery of the extracellular vesicles (EV) that they secrete.
2. The greatest therapeutic efficacy seems to be achieved by using secreting cells that are committed to the same lineage as those of the tissue to be repaired, hence, the use of cardiovascular progenitor cells as the source of the EV-enriched secretome.
3. Leveraging the benefits of cells, or their secreted products, by repeated administrations requires a non-invasive approach, which highlights the potential interest of the intravenous approach.

Inclusion Criteria:

1. Aged between 18 to 80 years
2. Signed written informed consent
3. French Social Security affiliation;
4. Dilated cardiomyopathy defined by a dilated LV with a reduced EF ≤40% on echocardiography and/or CMR imaging, unexplained by pressure or volume overload (severe arterial hypertension or significant valve disease), coronary artery disease (as assessed by coronary angiography) or a systemic disease; in case of chemotherapy-induced cardiomyopathy, patients should have a period of at least two years of clinical cancer-free state* and a low estimated likelihood of recurrence (≤30% at 5 years), as determined by an oncologist, based on tumor type, response to therapy, and negative metastatic work-up at the time of diagnosis (*exceptions to this are carcinoma in situ or fully resected basal and squamous cell cancer of the skin);
5. NYHA Class III in spite of optimal heart failure maximally tolerated guideline-directed medical therapy, including cardiac resynchronization if needed, without other treatment options;
6. Plasma level of B-type natriuretic peptide (BNP) > 150 pg/mL or, N-terminal pro-BNP (NT-proBNP) ≥ 400 pg/mL;
7. For child-bearing aged women, efficient contraception such as combined (estrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception associated with inhibition of ovulation and for men efficient contraception such as condom, during treatment and until the end of the relevant systemic exposure, i.e. until 3 months after the end of treatment.

Exclusion Criteria:

1. Implantation of a cardiac resynchronisation therapy device or an ICD unit during the preceding 3 months;
2. End-stage heart failure with reduced EF (HFrEF) defined as patients with American College of Cardiology Foundation/American Heart Association (ACCF/AHA) stage D (candidates for specialized interventions, including heart transplantation and mechanical assistance) or terminal HF (advanced HF with poor response to all forms of treatment, frequent hospitalizations and life expectancy < 12 months)
3. Patients treated with inotropic agents during the 1 month period prior to inclusion;
4. Acute heart failure (regardless of the cause);
5. Heart failure caused by cardiac valve disease, untreated hypertension or documented coronary artery disease with lesions which could explain the cardiomyopathy;
6. Cardiomyopathy due to a reversible cause e.g. endocrine disease, alcohol or drug abuse, myocarditis, Tako-Tsubo, or arrhythmias;
7. Cardiomyopathy due a syndromic/systemic disease (e.g. Duchenne's muscular dystrophy, immune/inflammatory/infiltrative disorders [amyloidosis, hemochromatosis]);
8. If post-chemotherapy cardiomyopathy: a history of radiation therapy AND evidence of constrictive physiology; a baseline computerized tomography scan or CMR showing new tumor or suspicious lymphadenopathy raising concern of malignancy; a trastuzumab treatment within the last 3 months;
9. Previous cardiac surgery;
10. Recent stroke (within the last 3 months);
11. Documented presence of a known LV thrombus, aortic dissection, or aortic aneurysm;
12. Uncontrolled ventricular tachycardia defined by sustained ventricular tachycardia, including electrical storm and incessant ventricular tachycardia with no response to antiarrhythmic medication; Internal Cardioverter Defibrillator firing in the 30 days prior to the first infusion;
13. History of drug-induced allergic reactions or allergy of any type having required treatment;
14. Contraindication to corticosteroids or anti-histaminic agents;
15. Contraindication to gadoterate meglumine if it will be used with CMR;
16. Hematological disease: anaemia (haematocrit < 25%), leukopenia (leucocytes < 2,500/μL) or thrombocytopenia (thrombocytes < 100,000/μL); myeloproliferative disorders, myelodysplastic syndrome, acute or chronic leukaemia, and plasma cell dyscrasias (multiple myeloma);
17. Coagulopathy not due to a reversible cause;
18. Diminished functional capacity for other reasons such as: Chronic Obstructive Pulmonary Disease (COPD) with Forced Expiratory Volume (FEV) <1 L/min, moderate to severe claudication or morbid obesity;
19. Diabetes with poorly controlled blood glucose levels and/or evidence of proliferative retinopathy;
20. Dialysis-dependent renal insufficiency;
21. Autoimmune disorders or current immunosuppressive therapy;
22. History of organ transplant or cell-based treatment;
23. Serum positivity for HIV, hepatitis BsAg, or viremic hepatitis C;
24. Female patient who is pregnant, nursing, or of child-bearing potential and not using effective birth control;
25. Active infection;
26. Known allergy to aminoglycosides;
27. Patient under legal protection (guardianship);
28. Participation in another interventional trial;
29. Life expectancy less than one year.
30. Contraindication to 18FDG-PETscan

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared

One year after the last publication

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Data sharing must respect agreements made with funders. Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization.

Processing of shared data must comply with European General Data Protection Regulation (GDPR)