A Randomized, Blinded, Placebo-Controlled Clinical Trial to Evaluate Longeveron Mesenchymal Stem Cell (LMSC) Therapy for Treating The Metabolic Syndrome

一项评估 Longeveron 间充质干细胞 (LMSC) 疗法治疗代谢综合征的随机、盲法、安慰剂对照临床试验

• 批准号: 9348026
• 负责人: Joshua M Hare
• 金额: $ 15万
• 依托单位: LONGEVERON, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348026
• 关键词: Address; Adult; Affect; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocyte Subsets; Biological Assay; Blinded; Blood Chemical Analysis; Blood Pressure; Cardiac; Cardiovascular system; Cell Therapy; Cells; Cholesterol; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Coagulation Process; Controlled Clinical Trials; Dobutamine; Dose; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Epidemic; Fasting; Female; Fibrin fragment D; Fibrinogen; Flow Cytometry; Glucose; Glycosylated hemoglobin A; Health Surveys; Hematology; High Density Lipoproteins; Incidence; Individual; Inflammation; Inflammatory; Infusion procedures; Insulin; Interleukin-1; Interleukin-6; International; Intravenous; Lead; Lipids; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Metabolic syndrome; Modeling; Monitor; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Phase; Physical Performance; Placebo Control; Placebos; Positioning Attribute; Property; Quality of life; Questionnaires; Randomized; Reaction; Reading; Risk; Running; SF-36; Safety; Sampling; Serious Adverse Event; Serum; Stem cells; Stress; Study Subject; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutic; Urinalysis; Urine; Vasodilation; Walking; blood glucose regulation; cardiovascular disorder risk; cytokine; effective therapy; endothelial dysfunction; fasting glucose; follow-up; immune activation; improved; indexing; inflammatory marker; insight; low density lipoprotein triglyceride; male; mortality; multipotent cell; patient population; phase 1 study; phase III trial; programs; Address; Adult; Affect; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocyte Subsets; Biological Assay; Blinded; Blood Chemical Analysis; Blood Pressure; Cardiac; Cardiovascular system; Cell Therapy; Cells; Cholesterol; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Coagulation Process; Controlled Clinical Trials; Dobutamine; Dose; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Epidemic; Fasting; Female; Fibrin fragment D; Fibrinogen; Flow Cytometry; Glucose; Glycosylated hemoglobin A; Health Surveys; Hematology; High Density Lipoproteins; Incidence; Individual; Inflammation; Inflammatory; Infusion procedures; Insulin; Interleukin-1; Interleukin-6; International; Intravenous; Lead; Lipids; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Metabolic syndrome; Modeling; Monitor; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Phase; Physical Performance; Placebo Control; Placebos; Positioning Attribute; Property; Quality of life; Questionnaires; Randomized; Reaction; Reading; Risk; Running; SF-36; Safety; Sampling; Serious Adverse Event; Serum; Stem cells; Stress; Study Subject; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutic; Urinalysis; Urine; Vasodilation; Walking; blood glucose regulation; cardiovascular disorder risk; cytokine; effective therapy; endothelial dysfunction; fasting glucose; follow-up; immune activation; improved; indexing; inflammatory marker; insight; low density lipoprotein triglyceride; male; mortality; multipotent cell; patient population; phase 1 study; phase III trial; programs

The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2 diabetes mellitus, and mortality, and currently affects > 40% of US adults. MetS is associated with endothelial dysfunction, decreased circulating endothelial progenitor cells (EPCs), and a pro-inflammatory state. We have made the exciting discovery that therapy with allogeneic mesenchymal stem cells (MSCs) restores endothelial dysfunction and circulating EPCs towards normal the levels, and reduces markers of inflammation. Endothelial function represents a key driver of cardiovascular morbidity and mortality in MetS, and as such, restoring endothelial function could lead to clinical benefits in this patient population. We will conduct a clinical trial using Longeveron-produced allogeneic mesenchymal stem cells (LMSCs) delivered to subjects with MetS. In Phase I of this study, we will perform a dose-escalation Safety Run-In to first establish safety of LMSC therapy in subjects with MetS. After a safety review and approval from an independent data safety monitoring board (DMSB), Phase II of this Fast-Track Study will commence. This will entail a Randomized, Double-Blinded, Placebo-Controlled Phase on 40 subjects with MetS. The following specific aims will be examined. Specific Aim #1: To test the hypothesis that LMSCs are safe to intravenously-administer to subjects with MetS. We will examine for incidence of treatment-emergent serious adverse events (TE-SAEs); blood chemistry, hematology, coagulation, and urinalysis; and alloimmune reaction and T and B cell subsets to examine levels of immune activation. Specific Aim #2: To test the hypothesis that intravenously-administered LMSCs will improve endothelial dysfunction and increase circulating EPCs in subjects with MetS. We will examine endothelial dysfunction using flow-mediated vasodilation (FMD), and circulating EPCs by colony assays and flow cytometry. Specific Aim #3: To test the hypothesis that intravenously-administered LMSCs will improve systemic markers of inflammation in subjects with MetS. We will use ELISA to examine panels of inflammatory markers. Specific Aim #4: To test the hypothesis that intravenously-administered LMSCs will lead to clinical improvement in subjects with MetS. We will examine for changes in glucose control (hemoglobin A1c, fasting glucose, fasting insulin, HOMA), lipid profile (HDL, LDL, triglycerides, cholesterol), blood pressure and cardiac function, physical performance, and subject quality of life. We anticipate that the results of this study will lead to a much needed therapeutic for subjects with MetS. Longeveron is positioned to rapidly advance this program to a pivotal phase III trial if the results prove positive, and to bring this technology to market.

代谢综合征（METS）是一群因素，增加了心血管疾病的风险，2型 糖尿病和死亡率，目前影响> 40％的美国成年人。大都会与内皮有关 功能障碍，循环内皮祖细胞（EPC）降低和促炎状态。我们有 令人兴奋的发现，同种异体间充质干细胞（MSC）的治疗恢复了内皮 功能障碍和循环EPC朝着正常的水平，并降低炎症标记。内皮 功能代表了大都会的心血管发病率和死亡率的关键驱动力，因此恢复 内皮功能可能会导致该患者人群的临床益处。我们将使用 长寿产生的同种异性间充质干细胞（LMSC）递送到具有MetS的受试者。在阶段 I在这项研究中，我们将执行剂量降低的安全性，以首先建立LMSC治疗的安全性 大都会的受试者。经过安全审查并获得了独立数据安全监控委员会的批准 （DMSB），这项快速研究的第二阶段将开始。这将需要一个随机，双盲， 安慰剂对照阶段在40名受试者中。将检查以下特定目标。 具体目的＃1：检验LMSC对具有静脉注射对受试者的静脉注射安全性的假设 大都会。我们将检查治疗生气的严重不良事件的发生率（TE-SAE）；血 化学，血液学，凝结和尿液分析；以及同种免疫反应以及T和B细胞亚群 检查免疫激活水平。 特定目的＃2：检验静脉注射液压的假设将改善内皮 功能障碍并增加具有MetS受试者的循环EPC。我们将检查内皮功能障碍 使用流动介导的血管舒张（FMD），并通过菌落测定和流式细胞仪循环EPC。 特定目的＃3：测试静脉注射LMSC的假设将改善系统性标记 大都会受试者的炎症。我们将使用ELISA检查炎症标记的面板。 特定目的＃4：检验静脉注射的LMSC的假设将导致临床 Mets受试者的改善。我们将检查葡萄糖控制的变化（血红蛋白A1C， 禁食葡萄糖，禁食胰岛素，HOMA），脂质剖面（HDL，LDL，甘油三酸酯，胆固醇），血压 和心脏功能，身体表现和学科生活质量。 我们预计这项研究的结果将为患有MetS的受试者带来急需的治疗。 如果结果证明为正，则寿命可以快速将该程序迅速推进至关键的III期试验。 并将这项技术推向市场。