Mesoblast Stem Cell Therapy for Patients With Single Ventricle and Borderline Left Ventricle

Study Overview
=================
Brief Summary
-----------------
Patients under the age of 5, with a diagnosis of hypoplastic left heart syndrome (HLHS), unbalanced atrioventricular canal (uAVC), or borderline left heart who are undergoing staged LV recruitment following bidirectional Glenn (BDG) or undergoing BDG with plans for LV recruitment will be considered for enrollment in this study. Those patients enrolled in the study will be randomized to either the experimental arm or control arm of the study. Those patients randomized to the experimental arm will receive mesenchymal precursor cells (MPCs) injected directly into the LV endocardium during their LV recruitment or BDG procedure. Those patients randomized to the control arm will receive normal standard of care during their procedure with no injection of MPCs. It is believed that injection of MPCs will help improve the chances of those patients with single ventricle or borderline left ventricle being converted to biventricular circulation which could improve quality of life and longevity over palliation.

Detailed Description
-----------------
This is a prospective, single center, safety and feasibility, blinded, randomized trial to evaluate the use of MPCs in children with complex cardiac anatomy requiring surgical repair. Patients scheduled to undergo bidirectional Glenn (BDG) with future plans for LV recruitment, or patients with a history of BDG who are currently scheduled to undergo LV recruitment will be eligible. Twenty-four subjects will be enrolled, 12 to the MPC treatment arm and 12 to the control arm following a 1:1 randomization schema. Randomization will be stratified according to surgeon to assure random distribution of subjects by surgeon. Families, the biostatistician, all clinical staff outside the operating room, and research staff completing data analysis will be blinded to randomization assignment. The PI, operating room staff, and research staff assisting with delivery will be unblinded to the randomization assignment. Families will be made aware of their randomization assignment once all subjects have completed their study Visit 4. Those randomized to the treatment arm will receive MPCs injected directly into the LV endocardium following clinical surgical maneuvers to recruit the LV (mitral valve repair, aortic valve repair, and/or resection of endocardial fibroelastosis) or BDG. Those subjects randomized to the control arm will receive standard LV recruitment or BDG with no injection. All cardiac tissue acquired as part of a clinically indicated procedure will be collected on enrolled subjects. Most of the tissue sample will be analyzed at the time of collection (histology and H+E stain); the remainder will be banked for potential future testing.

Official Title
-----------------
Mesoblast Stem Cell Therapy for Patients With Single Ventricle and Borderline Left Ventricle

Conditions
-----------------
Hypoplastic Left Heart Syndrome, Atrioventricular Canal

Intervention / Treatment
-----------------
* Biological: MPC; rexlemestrocel-L


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a history of single ventricle palliation (Stage 1 palliation, PA band, or hybrid procedure) undergoing bidirectional Glenn (BDG) with simultaneous left ventricle (LV) recruitment procedures or those patients undergoing LV recruitment procedures will be considered for enrollment. Exclusion Criteria: Patients with current or history of myocardial tumors Patients with aortic or mitral atresia Patients with a history of high grade ventricular arrhythmias Patients with a known allergy to dimethyl sulfoxide (DMSO) Patient has known allergy to mouse and/or cow products. Patient is prior recipient of stem cell therapy for cardiac repair. Patient has received treatment and/or is within an incomplete follow-up treatment of any investigational cell based therapy within 6 months prior to randomization.

Ages Eligible for Study
-----------------
Maximum Age: 5 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Those randomized to the treatment arm will receive MPCs injected directly into the LV endocardium following clinical surgical maneuvers to recruit the LV (mitral valve repair, aortic valve repair, and/or resection of endocardial fibroelastosis) or BDG. MPCs will be delivered directly into the LV endocardium via a 23-25 gauge needle following completion of all surgical procedures. A total dose of 20 million cells will be delivered, divided evenly into  11 injections of 50 µL each. The total volume is not to exceed 2.0 mL. | Biological: MPC; rexlemestrocel-L<br>* MPCs will be injected into the patient's myocardium during planned surgical procedures.<br>* Other names: Allogeneic Mesenchymal Precursor Cell;|
| No Intervention: Control Arm<br>Those subjects randomized to the control arm will receive standard LV recruitment or BDG with no injection. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety- Incidence of severe adverse events | Subjects will be SAE free for 24 months following injection of MPCs (in comparison of treatment arm to control arm. | 24 months | 
| Safety- Absence of PRA status change or local inflammation | Subjects will be free from Panel Reactive Antibody (PRA) status change for 24 months following injection of MPCs (in comparison of treatment arm to control arm). If there is a PRA of >5%, a donor specific antibody test will be completed, | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy- rate of biventricular conversion | Rate of those who are successfully converted to biventricular conversion in the treatment group compared to the control group. | 12 months | 
| Efficacy- improvement of LV end diastolic pressure | Rate of those who have improvement in these measurements in the treatment group compared to the control group. | 12 months | 
| Efficacy- improvement of LV mass/volume ratio | Rate of those who have improvement in these measurements in the treatment group compared to the control group. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
biventricular conversion