Clinical trial NCT02472002: Mesenchymal Stem Cell Administration in the Treatment of Coronary Graft Disease in Heart Transplant Patients
Official title: Mesenchymal Stem Cell Administration in the Treatment of Coronary Graft Disease in Heart Transplant Patients
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
PHASE2
Conditions: Coronary Disease
Heart Transplant
Keywords: Transplant coronary diseases
Mesenchymal cell therapy
Administration of CSM by NOGA system
Coronary disease in heart transplant patients
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2015-06-15
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: MES-HT is a pilot multicenter prospective study conducted in transplant patients who developed severe coronary vasculopathy. A preparation of autologous mesenchymal cells of bone marrow is administered by endomyocardial injection, guided by the Noga® cardiac mapping system.

The main objective is to determine the effect of the administration of autologous mesenchymal cells of the bone marrow by intramyocardial injection on myocardial perfusion in cardiac transplant patients with severe coronary vasculopathy.

Detailed description: MES-HT is a phase 1-2 multicenter pilot prospective study conducted on 14 heart transplant patients who developed severe coronary vasculopathy, in the aim to assess the effect on myocardial perfusion of the intramyocardial administration by percutaneous way of autologous mesenchymal stem cells derived from the bone marrow.

The main objective is to show improvement in myocardial perfusion in a non-randomized and uncontrolled pilot study, before considering a randomized controlled study. The administration of intra myocardial cells using the NOGA system was carried out to date with more than 1,000 patients and is considered feasible and safe. However, the investigators will assess very carefully the feasibility and safety of this invasive approach.

The primary endpoint is the improvement of myocardial perfusion measured by MRI after endomyocardial injection of mesenchymal cells by percutaneous way, guided by the NOGA system.

The secondary endpoints are the feasibility and safety of this administration, changes in ejection fraction measured by contrast echocardiography, changes in other MRI cardiac parameters (left ventricular volumes , intramyocardial fibrosis), the oxygen consumption during exercise, myocardial perfusion measured by SPECT. Other secondary endpoints are the evolution of the immune status, and histological criteria of myocardial biopsy.

Once the mapping performed, preparation is injected through another catheter (MYOSTAR injection catheter) which will also be guided by the Noga® system. This catheter may be positioned on the regions of interest (viable ischemic areas) and allow the injection of the quantity of CSM (40 million / ml) in 10 to 12 different injection points and injection volumes 0.3 ml for a total dose of 120 to 144 million cells.

After each injection procedure, patients are monitored for 48 hours minimum clinically and under continuous ECG monitoring to detect possible arrhythmias. A troponin dosage is done after 6 H, and after 24 and 48 hours. An echocardiogram is performed immediately after the procedure and before the release to 48 H.

A clinical evaluation will be made after the patient is discharged at 1 month (clinical examination + Holter + echocardiography), 3 months (examination), 6 months (clinical examination, Holter, echocardiography, cardiac MRI, test of effort with measurement of VO2, effort myocardial tomoscintigraphy and for patients from Pitie-Salpetriere hospital, Rubidium 82 by positron emission tomography) and 12 months (examination). Myocardial biopsy and a control coronary angiography will be only performed within 12 months in accordance with the practice of the teams.

Patients will benefit from a biological monitoring which provides for the monitoring of immune response. This immuno-monitoring is to assess the possible influence of the injection of mesenchymal cells on immunological tolerance mechanisms. It will be implemented in the balance sheets of cardiac tissue at the waning annual biopsies and peripheral blood samples on inclusion, 48 hours after injection and at 1 month, 3 months and 6 months.

The limiting toxicity is defined as the occurrence at one month of a serious adverse effect related to the protocol , requiring an hospitalization or being able to be life-threatening , or like abundant pericardial effusion requiring pericardial drainage, bleeding complications requiring blood cell transfusion or surgery, stroke constituted, sepsis or septic shock, cardiogenic shock, severe ventricular rhythm refractory death.

All patients are followed for one year.

Eligibility criteria: Inclusion criteria :

1. Cardiac transplant patient whatever is his initial pathology
2. Coronary vasculopathy grade 3 (CAV3) defined by:

   Stenosis \> 50% of common-core (CT) or stenosis \>70% of at least 2 or 3 main coronary arteries or stenosis \> 70% on secondary branches of 3 territories.

   Coronary vasculopathy grade 1 or 2 (CAV 1 or 2) associated with FELV (FEVG) dysfunction \<45% or abnormality of completion of restrictive type.
3. Defect of drip on at least 2 segments/17 in stress MRI.
4. Fraction of ejection LV\<50 measured on ultrasound examination or confusion of diastolic function defined by a restrictive mitral steam (E/A \> 2 or E/A between 1 and 2 and deceleration time E \< 150 ms) or left ventricular diastolic pressure measured during coronarography \>16mg Hg .
5. Without sign of acute rejection at the time of inclusion.
6. Under an optimal medical treatment
7. Patient who have given his enlightened and signed consent

Exclusion criteria :

1. Patients \<18 ou \>80 years
2. Acute coronary syndrome or revascularisation in the 3 last months
3. Acute cardiac rejection in the 3 last months
4. Atrial fibrillation
5. Claustrophobia or contraindication to MRI (ex:pace-maker), to contrast injection or adenosine.
6. Presence of a thrombus in the left cavities detected by ultra-sound examination or MRI realized before the injection..
7. Pregnant or breast-feeding woman
8. Woman old enough to reproduction without effective means of contraception during its participation in the study
9. Patient benefiting from a legal protective measure
10. HIV positive
11. Not membership in a national save insurance (beneficiary or legal successor)
12. Patients undergoing others biomedical research
13. Patient not understanding the procedure bound to the protocol
14. Bad adhesion to the protocol suspected by the investigator.

Primary outcomes:
measure: myocardial perfusion measured in MRI.
timeFrame: 6 months
Secondary outcomes:
measure: complications of catheterization
timeFrame: 6 months
measure: complications of endomyocardial injection
timeFrame: 6 months
measure: systolic function
timeFrame: 6 months
measure: diastolic function
timeFrame: 6 months
measure: immunomodulation induced MSCs in the blood
timeFrame: 6 months
measure: immunomodulation induced MSCs in myocardial biopsy
timeFrame: 6 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Département de cardiologie du Pr Michel KOMADJA
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Richard Isnard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: