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

项目摘要/摘要 特发性肺纤维化的其他治疗方法的开发是人类健康的迫切需要。我们 已确定表没食子儿茶素没食子酸酯(EGCG)是转化生长因子β-1反应的有效(IC50~50-100 nM)阻断剂 博莱霉素肺纤维化模型的体外和体内新的胶原沉积。EGCG是一名委托人 绿茶的主要成分，已被用于多项人体研究。我们已经给他注射了EGCG 肺纤维化患者在接受肺活检前两周，并高度显示 肺组织促纤维化标志物的显著逆转和转化生长因子β-1血液生物标志物的降低 发信号。然而，在FDA批准的同时，EGCG还没有被用于IPF患者 九替丹尼或吡非尼酮的IPF治疗和EGCG安全性的测定 由于EGCG相关肝毒性的报道很少。这项提案的首要目标是 目的：明确EGCG治疗特发性肺间质纤维化的安全性和最佳剂量。我们将使用R61/R33机制来 进行稳健的随机对照I期试验以获得额外的关键安全性和生物标记物数据 足以使第二阶段临床试验能够评估EGCG对特发性肺纤维化患者的疗效。总共5个 6个临床站点的10名IPF患者将被纳入接受EGCG的队列。在目标1中，我们将确定 特发性肺间质纤维化患者每日1次口服400 mg和600 mg EGCG12周的安全性 九替达尼或吡非尼酮。我们还将确定400毫克或600毫克的EGCG是否影响奈替达尼或吡非尼酮 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 肝毒性，将在12周的治疗期间和4周的随访期间密切监测。在……里面 目的2，我们将测量预先指定的血清生物标记物水平的变化，包括COMP、Periostin和 用EGCG治疗PRO-MMP1以确定是否存在EGCG效应的体内信号。最后，在目标3中，我们 将利用I型胶原特异的PET探针68Ga-CBP8来确定EGCG在减重中的影响 肺积聚。目标2和目标3的结果将提供有关剂量选择的关键信息。这 该提案利用了一个多主体研究团队的专业知识，这些团队是纤维化生物学和 临床试验设计，低成本干预，以及创新的分子探针。这一信息的全部内容 将提供设计第二阶段所需的关键信息，最终目标是开发急需的IPF 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.