Treatment of Non-ischemic Cardiomyopathies by Intravenous Extracellular Vesicles of Cardiovascular Progenitor Cells

NCT ID: NCT05774509

Last Updated: 2023-09-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-31
• Study Completion Date: 2026-07-15

Brief Summary

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?

Detailed Description

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.

Conditions

Heart Failure With Reduced Ejection Fraction

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treated group

A maximum of 12 patients will be included in the study following a dose-escalating design:

• Cohort 1 (4 patients) will receive 20x10E9 particles/kg for each infusion, with a total of 3 infusions, for a cumulative dose of 60x10E9 particles/kg;
• Cohort 2: in the absence of safety issues in Cohort 1, 8 patients will receive 40x10E9 particles/kg for each infusion, with a total of 3 infusions, for a cumulative dose of 120x10E9 particles/kg.

Group Type: EXPERIMENTAL

Extracellular vesicle-enriched secretome of cardiovascular progenitor cells differentiated from induced pluripotent stem cells

Intervention Type: BIOLOGICAL

Repeated (X3) intravenous infusions of the extracellular vesicle-enriched secretome of cardiovascular progenitor cells (differentiated from human induced pluripotent stem cells)

Interventions

Extracellular vesicle-enriched secretome of cardiovascular progenitor cells differentiated from induced pluripotent stem cells

Repeated (X3) intravenous infusions of the extracellular vesicle-enriched secretome of cardiovascular progenitor cells (differentiated from human induced pluripotent stem cells)

Intervention Type: BIOLOGICAL

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe Menasché, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Hôpital européen Georges Pompidou

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Touria EL AAMRI

Role: CONTACT

touria.el-aamri@aphp.fr

+33140271848

Sabrina BOUDIF

Role: CONTACT

sabrina.boudif@aphp.fr

+33156092920

Facility Contacts

Philippe MENASCHE, MD, PhD

Role: primary

philippe.menasche@aphp.fr

References

Kervadec A, Bellamy V, El Harane N, Arakelian L, Vanneaux V, Cacciapuoti I, Nemetalla H, Perier MC, Toeg HD, Richart A, Lemitre M, Yin M, Loyer X, Larghero J, Hagege A, Ruel M, Boulanger CM, Silvestre JS, Menasche P, Renault NK. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant. 2016 Jun;35(6):795-807. doi: 10.1016/j.healun.2016.01.013. Epub 2016 Jan 19.

Reference Type: BACKGROUND

PMID: 27041495 (View on PubMed)

El Harane N, Kervadec A, Bellamy V, Pidial L, Neametalla HJ, Perier MC, Lima Correa B, Thiebault L, Cagnard N, Duche A, Brunaud C, Lemitre M, Gauthier J, Bourdillon AT, Renault MP, Hovhannisyan Y, Paiva S, Colas AR, Agbulut O, Hagege A, Silvestre JS, Menasche P, Renault NKE. Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J. 2018 May 21;39(20):1835-1847. doi: 10.1093/eurheartj/ehy012.

Reference Type: BACKGROUND

PMID: 29420830 (View on PubMed)

Lima Correa B, El Harane N, Gomez I, Rachid Hocine H, Vilar J, Desgres M, Bellamy V, Keirththana K, Guillas C, Perotto M, Pidial L, Alayrac P, Tran T, Tan S, Hamada T, Charron D, Brisson A, Renault NK, Al-Daccak R, Menasche P, Silvestre JS. Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts. Cardiovasc Res. 2021 Jan 1;117(1):292-307. doi: 10.1093/cvr/cvaa028.

Reference Type: BACKGROUND

PMID: 32049348 (View on PubMed)

Lima Correa B, El Harane N, Desgres M, Perotto M, Alayrac P, Guillas C, Pidial L, Bellamy V, Baron E, Autret G, Kamaleswaran K, Pezzana C, Perier MC, Vilar J, Alberdi A, Brisson A, Renault N, Gnecchi M, Silvestre JS, Menasche P. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics. 2021 Nov 2;11(20):10114-10124. doi: 10.7150/thno.62304. eCollection 2021.

Reference Type: BACKGROUND

PMID: 34815807 (View on PubMed)

Humbert C, Cordier C, Drut I, Hamrick M, Wong J, Bellamy V, Flaire J, Bakshy K, Dingli F, Loew D, Larghero J, Fabreguettes JR, Menasche P, Renault NK, Churlaud G. GMP-Compliant Process for the Manufacturing of an Extracellular Vesicles-Enriched Secretome Product Derived From Cardiovascular Progenitor Cells Suitable for a Phase I Clinical Trial. J Extracell Vesicles. 2025 Aug;14(8):e70145. doi: 10.1002/jev2.70145.

Reference Type: DERIVED

PMID: 40831309 (View on PubMed)

Other Identifiers

2022-001844-75

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC-19-0330

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

APHP200034

Identifier Type: -

Identifier Source: org_study_id