This application for the Allogeneic Human Mesenchymal Stem Cell (MSC) Injection in Patients with Hypoplastic Left Heart Syndrome: A Phase IIb Clinical Trial (ELPIS) Clinical Coordinating Center (CCC) is collaborative with the ELPIS Data Coordinating Center (DCC) application. The CCC will have ultimate responsibility for managing the ELPIS clinical consortium of six clinical sites, meeting, planning enrollment milestones, distributing CCC resources, and overseeing all aspects of clinical design of the studies. Hypoplastic Left Heart Syndrome (HLHS) is one of the most complex forms of congenital heart disease (CHD), with a reported incidence of 0.2 per 1000 live births or 3% of children born with CHD. Once a universally fatal diagnosis, dramatic improvements in three staged palliative operations now allow the single right ventricle (RV) to functionally support the circulation. Despite these strides in medical care, the mortality rate of these infants remains as high as 25 to 35 percent during the first year of life and continues with a high mortality rate for the rest of their life. Those surviving childhood are likely to progress towards cardiac transplantation, usually due to failure of the systemic RV. To address this RV dysfunction, our stem cell trial is based on a decade of basic research and the ELPIS Phase I study using allogeneic MSCs in HLHS patients at the Stage II operation. Our completed enrolled ELPIS Phase I study supports both the feasibility for this investigative strategy and the safety profile of the allogeneic MSCs. Secondary endpoints demonstrated that the initial MSC treated patients showed by cardiac MRI (CMR) no difference in RV ejection fraction, or end diastolic volumes, however a significant decrease in RV mass was present, a surrogate for decreased hypertrophy. Our hypothesis for this trial is that intramyocardial delivery of allogeneic MSCs will improve the performance of the single systemic RV in HLHS patients at the Stage II operation. A total of 36 HLHS patients who are undergoing the Stage II operation will be single blinded and randomized to either receive MSC treatment or standard of care. Patients will be followed for one year. The primary outcome measurement will be decrease in RV mass as determined by CMR studies at baseline, 6 and 12 months following MSC injection. Secondary outcomes will include improvements in clinical and physiologic endpoints, improvements seen by other global RV cardiac function parameters measured by serial CMR studies, exosome biomarker analysis and safety endpoints. This single blinded randomized clinical trial is designed to address the following specific aims: (1) to analyze MSC delivery for RV function improvement at the Stage II operation; (2) to determine dynamic changes of the amount and composition of plasma biomarkers derived from the transplanted MSCs; and (3) to analyze safety of MSC treatment. Although not planned as a survival study, we anticipate that the proposed study will provide valuable data on the safety and benefit of MSC treatment in HLHS patients. The sufficiently definitive information will inform the decision on whether to proceed with a Phase III clinical trial of therapeutic MSC delivery to reduce mortality in HLHS patients and to direct its study design.
Hypoplastic left heart syndrome (HLHS) is one of the most complex forms of congenital heart disease (CHD), with a reported incidence of 0.2 per 1000 live births, or 3% of children born with CHD. Once a universally fatal diagnosis, dramatic improvements in three staged palliative operations now allow the single right ventricle (RV) to functionally support the total circulation. Despite these strides in medical care, the mortality rate of these infants remains as high as 25 to 35% during the first year of life and continues with a high mortality rate for the rest of their life. High mortality may in part be related to RV performance in these challenging infants. The major objective of the proposed study is to assess for the first time in a single blinded randomized control trial (RCT), whether intramyocardial injection of MSCs is beneficial for HLHS patients. The study is randomized so that during the Stage II operation, half the patients will receive MSC treatment and the other half will receive standard of care. The two groups will receive the same care thereafter and CMR will be used to assess RV performance.
