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，以支持计划中的未来P01应用，在人类受试者中使用表儿茶素干预。已经制定了一项研究计划，其最终目标是批准联邦药物管理局(FDA)批准研究用新药(IND)。IND的批准将允许使用(/-)-表儿茶素(即表儿茶素外消旋体)进行临床研究。该计划围绕以下6个主要目标(AIMS)构建：目标1.完成IND前咨询包，提交给FDA。参与的科学家将准备一份IND前申请包，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。目的2.用(/-)-表儿茶素进行啮齿动物和/或狗的药代动力学(PK)研究。未来的人类剂量优化研究可能需要在动物身上进行初步研究，以确定被认为可能对外消旋表儿茶素混合物有效的剂量范围。目的3.聘用外部承包服务，使用(/-)-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/或狗身上进行为期28天的毒理学研究，以评估(/-)-表儿茶素的安全性，这些数据可能对其随后在人类身上的使用至关重要。目的4.根据以上收集的信息和结果，向FDA提交IND申请，以进行第一阶段研究。研究小组将收集所有相关信息和结果，以便向FDA提交IND申请，以在人体上实施第一阶段研究。目的5.第一阶段研究：对受试者进行(/-)-表儿茶素的单剂量和多剂量PK和药效学(PD)分析，以确定安全的剂量范围。在一天的研究中，人类受试者将被给予(/-)-表儿茶素(最多六个增量剂量之一)，并连续采集血液样本。对于7天的研究，每天重复服用(/-)-表儿茶素，并连续采集血液样本。主要结果将是安全措施(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。次要结果将是血脂、葡萄糖和胰岛素浓度，以及全身炎症的标志。目标5包括应急计划(分目标A和B)，以防FDA不要求进行动物研究。Aim 5A将使用采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。目的6.根据以上收集的所有信息和第一阶段结果(目标5)，向FDA提交IND申请，以进行长期的人类临床研究。拟议的计划最终将允许研究团队收集关键的临床前和临床信息，这些信息被认为是FDA批准使用表儿茶素外消旋体在人类受试者中进行长期研究时可能需要的。

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.