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

同种异体人骨髓间充质干细胞(MSC)注射在发育不良患者中的应用 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将承担最终管理责任。 由六个临床站点组成的ELPIS临床联盟，开会，规划登记里程碑，分发CCC 资源，并监督研究的临床设计的所有方面。左心发育不良综合征(HLHS) 是最复杂的先天性心脏病(CHD)之一，据报道发病率为0.2/1000 活产儿占先天先天性心脏病患儿的3%。曾经是一个普遍致命的诊断，在三个方面有了戏剧性的改善 阶段性姑息性手术现在允许单个右室(RV)从功能上支持循环。 尽管在医疗保健方面取得了这些进展，但这些婴儿的死亡率仍然高达25%至35% 在生命的第一年期间，并在其余生中继续保持高死亡率。那些幸存的人 儿童可能会进展到心脏移植，通常是由于全身RV的故障。至 为了解决这种RV功能障碍，我们的干细胞试验基于十年的基础研究和Elpis I期 同种异体骨髓间充质干细胞在HLHS患者II期手术中的应用研究我们已完成的注册ELPIS阶段 我的研究支持这种研究策略的可行性和同种异体骨髓间充质干细胞的安全性。 次级终点显示，最初接受MSC治疗的患者心脏MRI(CMR)显示NO 右室射血分数或舒张末容量的差异，然而右室质量显著减少 目前，它是减少肥厚的替代品。我们对这项试验的假设是心肌内递送 异基因骨髓间充质干细胞将改善II期HLHS患者单一全身性RV的性能 手术。共36名正在接受第二阶段手术的HLHS患者将采用单盲和 随机接受MSC治疗或标准护理。患者将接受为期一年的跟踪调查。这个 主要结果测量将由基线CMR研究确定的RV质量减少，6和 MSC注射后12个月。次要结果将包括临床和生理方面的改善。 终点，通过连续CMR研究测量的其他全球RV心功能参数所见的改善， 外体生物标记物分析和安全终点。这项单盲随机临床试验旨在 解决以下具体目标：(1)在第二阶段分析用于房车功能改进的MSC交付 手术；(2)测定血浆生物标志物的数量和组成的动态变化 移植的骨髓间充质干细胞；(3)分析骨髓间充质干细胞治疗的安全性。尽管没有计划作为生存研究， 我们预计拟议的研究将提供有关MSC治疗的安全性和益处的有价值的数据 HLHS患者。充分确定的信息将为是否继续进行某一阶段的决策提供信息 III治疗性MSC给药降低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.