Early Phase Pre-Clinical and Initial Clinical Research on Epicatechin

该奖项的主要目标是资助早期临床前工作和初步临床研究，以支持计划的未来 P01 应用，使用基于表儿茶素的干预人类受试者。一项研究计划已经制定，其最终目标是获得联邦药物管理局 (FDA) 的研究性新药 (IND) 批准。 IND 批准将允许使用 (/-)-表儿茶素（即表儿茶素外消旋体）实施临床研究。该计划围绕 6 个主要目标（目标）构建，如下： 目标 1. 完成 IND 前咨询包并提交给 FDA。参与的科学家将准备一份预 IND 申请包，以便与 FDA 协商，以确定未来 IND 提交和批准所需的信息和数据。目标 2. 使用 (l-)-表儿茶素在啮齿动物和/或狗中进行药代动力学 (PK) 研究。未来的人类剂量优化研究可能需要在动物中进行初步研究，以确定可能对外消旋表儿茶素混合物有效的剂量范围。目标 3. 聘请外部承包服务，利用 (/-)-表儿茶素对啮齿动物和/或狗进行毒理学研究。将在啮齿动物和/或狗中进行为期 28 天的毒理学研究，以评估 (i)-表儿茶素的安全性，这些数据可能对其随后在人类中的使用至关重要。目标 4. 根据上述收集的信息和结果，向 FDA 提交 IND 申请以进行 I 期研究。研究团队将收集所有相关信息和结果，以便向 FDA 提交 IND 申请，以在人体中实施 I 期研究。目标 5. I 期研究：在人类受试者中进行 (l-)-表儿茶素的单剂量和多剂量 PK 和药效 (PD) 分析，以确定安全剂量范围。对于一日研究，人类受试者将接受 (l-)-表儿茶素（最多六种增量剂量之一）并连续采集血液样本。对于 7 天的研究，将进行每天重复的 (l-)-表儿茶素给药，并且还连续采集血液样本。主要结果是安全措施（例如心电图、血压、临床化学）以及血液和尿液中表儿茶素的浓度。次要结果是脂质、葡萄糖和胰岛素浓度以及全身炎症标志物。目标 5 包括应急计划（子目标 A 和 B），以防 FDA 不要求进行动物研究。目标 5A 将使用收集的血液样本来确定巨噬细胞的极性和细胞因子分泌的调节。 Aim 5B 将使用收集的血清样本进行代谢组学分析并测试线粒体功能改变的证据。目标 6. 根据上述收集的所有信息和 I 期结果（目标 5），向 FDA 提交 IND 申请，以进行人体长期临床研究。拟议的计划最终将使研究团队能够收集 FDA 认为可能需要的关键临床前和临床信息，以批准使用表儿茶素外消旋体对人类受试者进行长期研究。

The major objective of this award is to fund early phase pre-clinical work and initial clinical research in support of a planned future P01 application using an epicatechin based intervention in human subjects. A research plan has been developed whose ultimate goal is the granting of an Investigational New Drug (IND) approval by the Federal Drug Administration (FDA). An IND approval would allow the implementation of clinical studies using (+/-)-epicatechin (i.e., epicatechin racemate). The plan is structured around 6 major goals (aims) as follows: Aim 1. Complete a pre-IND consultation package to be submitted to the FDA. Participating scientists will prepare a pre-IND application package for consultation with the FDA to ascertain the information and data required for a future IND submission and approval. Aim 2. Pursue pharmacokinetic (PK) studies in rodents and/or dogs using (+/-)-epicatechin. Future dose optimization studies in humans may require initial studies in animals to identify a dose range deemed likely to be effective for the racemic epicatechin mixture. Aim 3. Employ outside contracting services to pursue toxicology studies in rodents and/or dogs using (+/-)-epicatechin. A 28-day toxicology study in rodents and/or dogs will be implemented to evaluate the safety of (+/-)-epicatechin, data that may be essential for its subsequent use in humans. Aim 4. Based upon the above collected information and results, submit an IND application to the FDA in pursuit of phase I studies. The research team will collect all relevant information and results for the submission of an IND application to the FDA to implement phase I studies in humans. Aim 5. Phase I studies: Perform single and multi-dose PK and pharmacodynamic (PD) analysis of (+/-)-epicatechin in human subjects to determine a safe dosing range. For one day studies, human subjects will be given (+/-)-epicatechin (one of up to six incremental doses) and blood sampled serially. For 7 day studies, repeated daily dosing with (+/-)-epicatechin will take place and blood also sampled serially. Primary outcomes will be safety measures (e.g., electrocardiogram, blood pressure, clinical chemistry) and concentrations of epicatechin in blood and urine. Secondary outcomes will be lipids, glucose and insulin concentrations, and markers of systemic inflammation. Aim 5 includes contingency plans (sub aims A and B) in case animal studies are not required by the FDA. Aim 5A will use blood samples collected to ascertain macrophage polarity and regulation of cytokine secretion. Aim 5B will use serum samples collected to perform metabolomics profiling and test for evidence of altered mitochondrial function. Aim 6. Based upon all of the above collected information and Phase I results (Aim 5), submit an IND application to the FDA in pursuit of long-term clinical studies in humans. The proposed plan will ultimately allow the research team to gather critical pre-clinical and clinical information deemed likely to be required by the FDA in granting approval for longer-term studies in human subjects using the epicatechin racemate.