Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure (ESCORT)

Transplantation of Human Embryonic Stem Cell-derived CD15+ Isl-1+ Progenitors in Severe Heart Failure

The purpose of the study is to assess the feasibility and safety of a transplantation of cardiac-committed progenitor cells derived from human embryonic stem cells in patients with severe heart failure.

Study Overview

• Status: Completed
• Conditions: Ischemic Heart Disease
• Intervention / Treatment: Biological: Human embryonic stem cell-derived CD15+ Isl-1+ progenitors

Detailed Description

Heart failure due to coronary artery disease is a major problem because of its high prevalence, increased incidence and associated costs. When conventional medical/interventional treatments fail and if cardiac transplantation is contra-indicated, alternate options need to be considered. Transplantation of stem cells has emerged as one of them. While the optimal cell type still remains debatable, there is compelling evidence that cells whose phenotype closely matches that of the recipient tissue look sound candidates. In this context, human embryonic stem cells are attractive because of the possibility to drive their fate in vitro, prior to transplantation, towards a cardiac phenotype. We have developed a process for achieving such a commitment and generating cardiac-directed cells. The objective of this study is to assess both the feasibility and safety of this approach. In addition, the disadvantages of multiple intramyocardial injections have now been recognized. We have then taken advantage of the surgical setting of the trial (which entails concomitant coronary artery bypass or a mitral valve procedure) to switch from injections to the epicardial delivery of a fibrin gel into which the progenitor cells have been embedded. Coverage of this cell-loaded patch by an autologous pericardial flap is finally designed to provide trophic factors to the underlying cellular graft with the hope of improving its viability.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Department of Cardiovascular Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 and less than 81 years
• Severe left ventricular systolic dysfunction with left ventricular ejection fraction (LVEF) ≤ 35% as assessed by echocardiography or scintigraphy
• History of myocardial infarction (older than 6 months) with a residual akinesia involving more than 2 (out of 16) contiguous segments, as assessed by basal echocardiography
• New York Heart Association (NYHA) Class III or IV despite optimal standard of care including diuretics and angiotensin receptor blockers and, if possible, beta blockers and aldosterone blockers
• Previous implantation of an automatic internal defibrillator associated, whenever indicated, to ventricular resynchronization
• Indication for a conventional cardiac surgical procedure : coronary artery bypass grafting involving, or not, the infarct area planned to be covered by the cell-loaded patch or mitral valve repair or replacement for ischemic mitral valve regurgitation; Non Eligibility to heart transplantation; Affiliation to a social security regimen
• Willingness and ability to give written informed consent

Exclusion Criteria:

• Pregnant or potentially child-bearing women
• Patients with poor echogenicity
• Left ventricular aneurysm
• Contra-indication to immunosuppressive drugs (history of cancer, infections like B or C hepatitis, positivity for Hepatitis-B, HIV, HTLV1)
• Contra-indication to sternotomy
• Alloimmunisation against the cell line from which the progenitors are derived
• Cardiogenic shock or NYHA Class IV heart failure requiring need for intravenous drugs
• Intellectual deterioration or psychiatric disease interfering with the ability to obtain an informed consent and to achieve a close follow-up of the patient
• Noncardiac disease which may reduce life expectancy in the short term
• Simultaneous participation to another trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Human embryonic stem cell; Patients with ischemic heart failure receiving a fibrin gel embedding human embryonic stem cell-derived CD15+ Isl-1+ progenitors in addition to coronary artery bypass grafting and/or a mitral valve procedure.	Biological: Human embryonic stem cell-derived CD15+ Isl-1+ progenitors; Epicardial delivery of a fibrin patch embedding human embryonic stem cell-derived CD15+ Isl-1+ progenitors

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number and nature of adverse events	Evidence for new clinical/biological abnormalities, occurrence of arrhythmias or development of a cardiac or extra-cardiac tumor.	Within the first year after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of patch's generation and its efficacy on cardiac functions	Feasibility will be assessed by the ability to generate hESC-derived CD15+ Isl-1+ progenitors according to preset quality measures, to incorporate these cells in a fibrin patch, to deliver this patch onto the epicardium of the infarct area and to cover it with an autologous pericardial flap. Efficacy will be assessed on the following end points : 1- left ventricular function; 2- viability of the grafted area; 3- functional status; 4- major adverse cardiovascular events.	Within the first year after surgery

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Philippe Menasché, MD, PhD, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Paris, France

Publications and helpful links

General Publications

• Puymirat E, Geha R, Tomescot A, Bellamy V, Larghero J, Trinquart L, Bruneval P, Desnos M, Hagege A, Puceat M, Menasche P. Can mesenchymal stem cells induce tolerance to cotransplanted human embryonic stem cells? Mol Ther. 2009 Jan;17(1):176-82. doi: 10.1038/mt.2008.208. Epub 2008 Oct 7.
• Menasche P, Vanneaux V, Hagege A, Bel A, Cholley B, Parouchev A, Cacciapuoti I, Al-Daccak R, Benhamouda N, Blons H, Agbulut O, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Charron D, Tartour E, Tachdjian G, Desnos M, Larghero J. Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. J Am Coll Cardiol. 2018 Jan 30;71(4):429-438. doi: 10.1016/j.jacc.2017.11.047.

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2013
• Primary Completion (Actual): March 22, 2018
• Study Completion (Actual): March 22, 2018

Study Registration Dates

• First Submitted: September 17, 2013
• First Submitted That Met QC Criteria: February 6, 2014
• First Posted (Estimate): February 7, 2014

Study Record Updates

• Last Update Posted (Actual): July 10, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Postinfarction heart failure; Transplantation of human embryonic stem cell-derived cardiac progenitors; Tissue-engineered cellular graft; Fibrin hydrogel
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Heart Failure; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia
• Other Study ID Numbers: P100303