1/2 Allogeneic Human Mesenchymal Stem Cell (MSC) Injection in Patients with Hypoplastic Left Heart Syndrome: A Phase IIb Clinical Trial

本申请为“异基因人间充质干细胞（MSC）注射在发育不良患者中” 左心综合征：IIb期临床试验（ELPIS）”临床协调中心（CCC）与 ELPIS数据协调中心（DCC）应用程序。CCC将最终负责管理 ELPIS临床联盟的六个临床研究中心，会议，计划招募里程碑，分发CCC 资源，并监督研究临床设计的各个方面。左心发育不良综合征（HLHS） 是先天性心脏病（CHD）最复杂的形式之一，据报道发病率为千分之0.2 活产或3%的先天性心脏病患儿。一旦普遍致命的诊断，戏剧性的改善，在三个 分期姑息手术现在允许单个右心室（RV）在功能上支持循环。 尽管在医疗保健方面取得了这些进步，这些婴儿的死亡率仍然高达25%至35 在生命的第一年，并在其余生中继续保持高死亡率。那些幸存者 儿童期的心脏移植可能进展到心脏移植，通常是由于系统性RV的失败。到 为了解决这种RV功能障碍，我们的干细胞试验是基于十年的基础研究和ELPIS I期， 在II期手术中使用同种异体MSC的HLHS患者的研究。我们已完成的入组ELPIS阶段 本研究支持这种研究策略的可行性和同种异体MSC的安全性。 次要终点表明，最初接受MSC治疗的患者通过心脏MRI（CMR）显示， RV射血分数或舒张末期容积的差异，但RV质量显著降低， 目前，一个替代减少肥大。我们对这项试验的假设是， 同种异体MSC将改善处于II期的HLHS患者的单个系统RV的性能 操作共36名正在接受II期手术的HLHS患者将接受单盲治疗， 随机接受MSC治疗或标准护理。患者将被随访一年。的 主要结局测量将是基线时CMR研究确定的RV质量降低，6和 MSC注射后12个月。次要结局将包括临床和生理方面的改善 终点，通过系列CMR研究测量的其他总体RV心脏功能参数观察到的改善， 外泌体生物标志物分析和安全性终点。本单盲随机临床试验旨在 解决以下具体目标：（1）分析MSC输送对II期RV功能改善的影响 （2）测定来自于以下的血浆生物标志物的量和组成的动态变化： （3）分析MSC治疗的安全性。虽然没有计划作为生存研究， 我们预计，这项研究将为MSC治疗的安全性和益处提供有价值的数据， HLHS患者。充分确定的信息将为决定是否继续进行某个阶段提供依据 III.治疗性MSC递送降低HLHS患者死亡率的临床试验，并指导其研究设计。

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.