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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Repeated (X3) intravenous infusions of the extracellular vesicle-enriched secretome of cardiovascular progenitor cells (differentiated from human induced pluripotent stem cells)
Hôpital européen Georges Pompidou
Paris, France
RECRUITINGSerious Adverse Events
Number of any potentially Serious Adverse Events (SAEs)/Reactions attributed to the experimental treatment: death (cardiovascular or of any cause), hospitalization for worsening heart failure, acute coronary syndrome (including myocardial infarction), sustained atrial and ventricular arrhythmias, ischemic stroke, immune-allergic or infectious reactions to the intravenous infusions of the IMP, and any other potential adverse effects detected and corroborated by clinical presentation, laboratory investigations and image analysis.
Time frame: 10 weeks after the onset of treatment: 6 weeks of treatment and 4 weeks of follow-up after the last IMP infusion.
Validation of the bioactivity of the EV-enriched secretome by proliferation of human vascular endothelial cells.
Bioactivity of the IMP (potency tests) assessed by proliferation of human vascular endothelial cells assessed by BrdU (\>20% relative to the control).
Time frame: 12 months
Validation of the bioactivity of the EV-enriched secretome by activation of allogeneic peripheral blood mononuclear cells.
Bioactivity of the IMP (potency tests) assessed by activation of allogeneic peripheral blood mononuclear cells assessed by the secretion of IL-2 and IFNγ (lack of increased secretion compared with the control).
Time frame: 12 months
Validation of the bioactivity of the EV-enriched secretome
Bioactivity of the IMP (potency tests) assessed by degranulation of Natural Killer cells assessed by the expression of CD107 (compared with a negative control).
Time frame: 12 months
Assessment of the effects of the IMP on immune and inflammatory responses at 3 weeks after the onset of the treatment.
Detection of donor-specific antibodies before the second secretome infusion.
Time frame: 3 weeks after the onset of the treatment.
Assessment of the effects of the IMP on immune and inflammatory responses at 6 weeks after the onset of the treatment.
Detection of donor-specific antibodies before the third secretome infusion.
Time frame: 6 weeks after the onset of the treatment.
Assessment of the effects of the IMP on immune and inflammatory responses at 10 weeks after the onset of the treatment.
Detection of donor-specific antibodies at 28 days following the last secretome infusion.
Time frame: 10 weeks after the onset of the treatment.
Assessment of the effects of the IMP on immune and inflammatory responses at 6 months after the last secretome infusion.
Detection of donor-specific antibodies at 6 months following the last secretome infusion if DSA are detected at the 28 days post-treatment study point at MFI ≥ 5000.
Time frame: 6 months after the last secretome infusion.
Inflammatory response to IMP infusions
Assessment of blood levels of interleukins, C- Reactive Protein and immune cells.
Time frame: 28 days, 6 and 12 months following the third infusion
Monitoring for Major Cardiovascular Adverse Events (MACE)
MACE including cardiac death, rehospitalization for heart failure, acute coronary syndromes, ischemic stroke and ventricular arrhythmias during the 1-year follow-up.
Time frame: 28 days following the last IMP infusion and subsequently until 1 year after the end of treatment
Changes in LV function assessed by NYHA at 28 days after the end of the treatment.
New York Heart Association (NYHA) functional class.
Time frame: 28 days after the end of the treatment.
Changes in LV function assessed by NYHA at 6 months after the end of the treatment.
New York Heart Association (NYHA) functional class.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by NYHA at 12 months after the end of the treatment.
New York Heart Association (NYHA) functional class.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by Minnesota Living With Heart Failure questionnaire at 6 months after the end of the treatment.
Quality of life assessed by Minnesota Living With Heart Failure questionnaire.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by Minnesota Living With Heart Failure questionnaire at 12 months after the end of the treatment.
Quality of life assessed by Minnesota Living With Heart Failure questionnaire.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by LV ejection fraction at 28 days after the end of the treatment.
Measurements of LV ejection fraction (EF%) by Doppler-echocardiography.
Time frame: 28 days after the end of the treatment.
Changes in LV function assessed by LV ejection fraction at 6 months after the end of the treatment.
Measurements of LV ejection fraction (EF%) by Doppler-echocardiography.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by LV ejection fraction at 12 months after the end of the treatment.
Measurements of LV ejection fraction (EF%) by Doppler-echocardiography.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by LV Volumes at 28 days after the end of the treatment.
LV Volumes ml/m2 by Doppler-echocardiography.
Time frame: 28 days after the end of the treatment.
Changes in LV function assessed by LV Volumes at 6 months after the end of the treatment.
LV Volumes ml/m2 by Doppler-echocardiography.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by LV Volumes at 12 months after the end of the treatment.
LV Volumes ml/m2 by Doppler-echocardiography.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by LV global longitudinal strain at 28 days after the end of the treatment.
LV global longitudinal strain (%) by Doppler-echocardiography.
Time frame: 28 days after the end of the treatment.
Changes in LV function assessed by LV global longitudinal strain at 6 months after the end of the treatment.
LV global longitudinal strain (%) by Doppler-echocardiography.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by LV global longitudinal strain at 12 months after the end of the treatment.
LV global longitudinal strain (%) by Doppler-echocardiography.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by LV ejection fraction (%) by Cardiac Magnetic Resonance at 6 months after the end of the treatment.
Measurements of LV ejection fraction (%) by Cardiac Magnetic Resonance.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by LV ejection fraction (%) by Cardiac Magnetic Resonance at 12 months after the end of the treatment.
Measurements of LV ejection fraction (%) by Cardiac Magnetic Resonance.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by LV volumes (ml/m2) by Cardiac Magnetic Resonance at 6 months after the end of the treatment.
LV volumes (ml/m2) by Cardiac Magnetic Resonance (CMR).
Time frame: 6 months after the end of the treatment.
Changes in LV function Changes in LV function assessed by LV volumes (ml/m2) by Cardiac Magnetic Resonance at 12 months after the end of the treatment.
LV volumes (ml/m2) by Cardiac Magnetic Resonance (CMR).
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by the presence/extent of myocardial late-enhancement at 6 months after the end of the treatment.
Presence/extent of myocardial late-enhancement after gadolinium administration, in the absence of contra-indication, by Cardiac Magnetic Resonance.
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by the presence/extent of myocardial late-enhancement at 12 months after the end of the treatment.
Presence/extent of myocardial late-enhancement after gadolinium administration, in the absence of contra-indication, by Cardiac Magnetic Resonance.
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by maximum oxygen consumption at 6 months after the end of the treatment.
Maximum oxygen consumption at exercise (mL/min/kg).
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by maximum oxygen consumption at 12 months after the end of the treatment.
Maximum oxygen consumption at exercise (mL/min/kg).
Time frame: 12 months after the end of the treatment.
Changes in LV function assessed by Natriuretic peptide plasma levels at 28 days after the end of the treatment.
Natriuretic peptide plasma levels (BNP or NT-ProBNP in pg/mL).
Time frame: 28 days after the end of the treatment.
Changes in LV function assessed by Natriuretic peptide plasma levels at 6 months after the end of the treatment.
Natriuretic peptide plasma levels (BNP or NT-ProBNP in pg/mL).
Time frame: 6 months after the end of the treatment.
Changes in LV function assessed by Natriuretic peptide plasma levels at 12 months after the end of the treatment.
Natriuretic peptide plasma levels (BNP or NT-ProBNP in pg/mL).
Time frame: 12 months after the end of the treatment.
Serious Adverse Events
Number of any potentially Serious Adverse Events (T-SAEs)/Reactions attributed to the experimental treatment (primary endpoint) up to 12 months.
Time frame: 12 months
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