Early Phase Pre-Clinical and Initial Clinical Research on Epicatechin

表儿茶素的早期临床前和初步临床研究

• 批准号: 8719394
• 负责人: Robert Roy Henry
• 金额: $ 64.27万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719394
• 关键词: Animals; Award; Blood; Blood Pressure; Blood specimen; Canis familiaris; Clinical; Clinical Chemistry; Clinical Research; Consultations; Contract Services; Data; Dose; Drug Kinetics; Electrocardiogram; Funding; Future; Glucose; Goals; Grant; Human; Inflammation; Insulin; Intervention; Investigational Drugs; Investigational New Drug Application; Lipids; Longitudinal Studies; Measures; Mitochondria; New Drug Approvals; Pharmaceutical Preparations; Pharmacodynamics; Phase; Regulation; Research; Rodent; Safety; Sampling; Scientist; Serum; Structure; Testing; Toxicology; Urine; Work; base; cytokine; epicatechin; human subject; macrophage; metabolomics; phase 1 study; pre-clinical; primary outcome; secondary outcome

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.

该奖项的主要目的是资助早期临床前工作和初步临床研究，以支持基于epicatechin的人类受试者的计划的未来P01应用。已经制定了一项研究计划，其最终目标是授予联邦药物管理局（FDA）批准的研究新药（IND）。 IND批准将允许使用（+/-） - epicatechin（即epicatechin Racemate）实施临床研究。该计划的结构约为6个主要目标（目标），如下所示：目标1。完成预定咨询套餐以提交给FDA。参与的科学家将准备一个预先申请包，以咨询FDA，以确定未来IND提交和批准所需的信息和数据。 AIM 2。使用（+/-） - epicatechin在啮齿动物和/或狗中进行药代动力学（PK）研究。未来在人类中的剂量优化研究可能需要在动物中进行初步研究，以鉴定可能对外消旋性上皮环激素混合物有效的剂量范围。 AIM 3。使用（+/-） - epicatechin在啮齿动物和/或狗中使用外部承包服务来从事毒理学研究。将对啮齿动物和/或狗进行28天的毒理学研究，以评估（+/-） - epicatechin的安全性，这对于随后在人类中的使用可能至关重要。目标4。根据上述收集的信息和结果，请在追求I期研究时向FDA提交IND申请。研究团队将收集所有相关信息和结果，以向FDA提交IND申请，以在人类中实施I期研究。 AIM 5。第一阶段研究：对人类受试者（+/-） - epicatechin进行单剂量和多剂量PK和药效学（PD）分析，以确定安全的给药范围。在一天的研究中，将给予人类受试者（+/-） - epicatechin（最多六个增量剂量）和血液采样串行。在7天的研究中，将每天重复服用（+/-） - Epicatechin将进行，血液也会连续采样。主要结果将是安全措施（例如心电图，血压，临床化学）和血液和尿液中epicatechin的浓度。次要结果将是脂质，葡萄糖和胰岛素浓度以及全身炎症的标志物。 AIM 5包括应急计划（SUB AIM A和B），以防FDA不需要动物研究。 AIM 5A将使用收集的血液样本来确定巨噬细胞极性和细胞因子分泌的调节。 AIM 5B将使用收集的血清样品进行代谢组学分析并测试线粒体功能改变的证据。目标6。基于上述所有收集的信息和第一阶段的结果（AIM 5），向FDA提交IND应用程序，以追求人类的长期临床研究。拟议的计划最终将允许研究团队收集FDA认为可能需要使用Epicatechin Recememate批准人类受试者的长期研究的关键临床前和临床信息。