Phase 1 study of oral epigallocatechin-3-gallate (EGCG) in IPF patients

项目总结/摘要 特发性肺纤维化的其他疗法的开发是人类健康的迫切需求。我们 已经鉴定出表没食子儿茶素-3-没食子酸酯（EGCG）是TGFβ1反应的有效（IC 50 ~ 50-100 nM）阻断剂 在肺纤维化的博来霉素模型中的离体和体内新胶原沉积。EGCG是一种 这种茶是绿色茶的主要成分，已用于多项人体研究。我们已经给予EGCG， 在接受肺活检前两周患有肺纤维化的患者， 肺组织中促纤维化标志物的显著逆转和TGFβ1血液生物标志物的降低 信号然而，在FDA批准的并发症背景下，尚未向IPF患者给予EGCG。 IPF治疗和在尼达尼布或吡非尼酮使用背景下测定EGCG的安全性， 必需的，因为很少报告EGCG相关的肝毒性。本提案的总体目标是 确定EGCG在IPF患者中的安全性和最佳剂量。我们将使用R61/R33机制， 进行一项稳健的随机对照I期试验，以获得额外的关键安全性和生物标志物数据 足以使II期临床试验能够评估EGCG在IPF患者中的疗效。共5 将在6个临床站点招募每组10名IPF患者的队列以接受EGCG。在目标1中，我们将确定 IPF患者口服400 mg和600 mg EGCG每日一次，持续12周，同时 尼达尼布或吡非尼酮。我们还将确定400 mg或600 mg EGCG是否影响尼达尼布或吡非尼酮 血液水平，以及这些抗纤维化药物是否会改变EGCG的血液水平。临床安全性，尤其是 在12周治疗期间和4周随访期间将密切监测肝毒性。在 目的2，我们将测量预先指定的血清生物标志物水平的变化，包括COMP、骨膜蛋白和 pro-MMP 1与EGCG处理以确定是否存在EGCG作用的体内信号。在目标3中，我们 将利用I型胶原特异性PET探针68 Ga-CBP 8来确定EGCG在减弱 肺蓄积目标2和3的结果将为剂量选择提供关键信息。这 该提案利用了多个主要研究者团队的专业知识，这些团队是纤维化生物学的领导者， 临床试验设计、低成本干预和创新的分子探针。这些信息的全部 将提供设计第二阶段所需的关键信息，其最终目标是制定急需的指规数 治疗

PROJECT SUMMARY / ABSTRACT The development of additional therapies for idiopathic pulmonary fibrosis is a pressing human health need. We have identified epigallocatechin-3-gallate (EGCG), as potent (IC50 ~ 50-100 nM) blocker of TGFβ1 responses ex vivo and new collagen deposition in vivo in the bleomycin model of pulmonary fibrosis. EGCG is a principal component of green tea and has been utilized in multiple human studies. We have administered EGCG to patients with pulmonary fibrosis for two weeks prior to undergoing lung biopsy and demonstrated highly significant reversal of pro-fibrotic markers in lung tissue and decreases in blood biomarkers of TGFβ1 signaling. However, EGCG has not been given to patients with IPF in the setting of concurrent FDA-approved IPF therapies and determination of the safety of EGCG in the setting of nintedanib or pirfenidone use is essential given infrequent report of EGCG associated hepatotoxicity. The overarching goal of this proposal is to define the safety and optimal dose of EGCG in IPF patients. We will use the R61/R33 mechanism to conduct a robust randomized controlled Phase I trial to obtain additional critical safety and biomarker data sufficient to empower a Phase II clinical trial to assess the efficacy of EGCG in IPF patients. A total of 5 cohorts of 10 IPF patients each at 6 clinical sites will be enrolled to receive EGCG. In Aim 1, we will determine the safety of oral 400 mg and 600 mg EGCG given once daily to IPF patients for 12 weeks concurrent with nintedanib or pirfenidone. We will also determine if 400 mg or 600 mg EGCG impacts nintedanib or pirfenidone blood levels, and whether these antifibrotics alter the blood levels of EGCG. Clinical safety, especially hepatotoxicity, will be monitored closely during the 12 week treatment duration and the 4 weeks of follow-up. In Aim 2, we will measure the change in levels of prespecified serum biomarkers including COMP, Periostin, and pro-MMP1 with EGCG treatment to determine if there is an in vivo signal for EGCG effect. Lastly, in Aim 3, we will utilize the type I collagen-specific PET probe, 68Ga-CBP8 to determine the impact of EGCG in attenuating lung accumulation. The results of Aim 2 and 3 will provide crucial information as to dose selection. This proposal leverages the expertise of a multi-principal investigator team that are leaders in fibrosis biology and clinical trial design, a low cost intervention, and an innovative molecular probe. The totality of this information will provide key information needed to design a phase II with the ultimate goal of developing much needed IPF therapies.