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

IPF 患者口服表没食子儿茶素-3-没食子酸酯 (EGCG) 的 1 期研究

• 批准号: 10418169
• 负责人: Harold A Chapman
• 金额: $ 45.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418169
• 关键词: Acute; Attenuated; Binding; Biological Markers; Biology; Biopsy; Blood; Chemistry; Clinical; Clinical Trials; Clinical Trials Design; Collagen; Collagen Type I; Consumption; Data; Deposition; Development; Diagnostic; Disease; Dose; Double-Blind Method; Enrollment; Ensure; Epigallocatechin Gallate; Epithelial; Exhibits; FDA approved; Family; Fibrillar Collagen; Fibroblasts; Fibrosis; Future; Goals; Green tea; Health; Hepatic; Hepatotoxicity; Human; Image; In Vitro; Inflammation; Interstitial Collagenase; Interstitial Lung Diseases; LOX gene; LOXL2 gene; Laboratories; Link; Lung; Measures; Modeling; Molecular Probes; Monitor; Mus; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Physiological; Pilot Projects; Pirfenidone; Placebo Control; Placebos; Plants; Population; Positron-Emission Tomography; Principal Investigator; Progressive Disease; Protein-Lysine 6-Oxidase; Pulmonary Fibrosis; Randomized; Renal function; Reporting; Role; Safety; Serum; Signal Transduction; Structure of parenchyma of lung; Surrogate Markers; Testing; Time; Tissues; Toxic effect; antifibrotic treatment; clinical research site; cohort; crosslink; design; drug development; effective therapy; follow-up; high throughput screening; idiopathic pulmonary fibrosis; in vivo; indium-bleomycin; inhibitor; injured; innovation; insight; intervention cost; nanomolar; nintedanib; novel; patient subsets; periostin; phase 1 study; phase 2 study; phase I trial; phase II trial; pre-clinical; preclinical study; response; small molecule; therapeutic target; treatment duration

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.

项目摘要 /摘要 开发针对特发性肺纤维化的其他疗法是人类健康需求。我们 已经确定了epigallocatechin-3-gallate（EGCG），为TGFβ1响应的电势（IC50〜50-100 nm） 肺纤维化博来霉素模型中的体内体内沉积和新的胶原蛋白沉积。 EGCG是校长 绿茶的成分，已用于多项人类研究。我们已经管理EGCG 肺纤维化患者在进行肺活检前两周 肺组织中促纤维标志物的显着逆转和TGFβ1的血液生物标志物的下降 信号。但是，在同一FDA批准的情况下，尚未将EGCG给予IPF患者 IPF疗法和在Nintedanib或Pirfenidone使用中的EGCG安全性的确定是 鉴于EGCG相关的肝毒性的不经常报告。该提议的总体目标是 定义IPF患者中EGCG的安全性和最佳剂量。我们将使用R61/R33机制来 进行强大的随机控制阶段试验以获取其他关键安全和生物标志物数据 总共5个 将在6个临床部位的10名IPF患者的同类人群招募接受EGCG。在AIM 1中，我们将确定 口服400 mg和600 mg EGCG的安全性每天给IPF患者一次，同时12周 我们还将确定400 mg或600 mg EGCG会影响Nyntedanib或Pirfenidone 血液水平以及这些抗纤维蛋白是否改变了EGCG的血液水平。尤其是临床安全 肝毒性将在12周的治疗持续时间和随访4周期间密切监测。在 AIM 2，我们将衡量预先指定的血清生物标志物水平的变化，包括Comp，Pererostin和 pro-MMP1进行EGCG处理，以确定是否存在EGCG效应的体内信号。最后，在AIM 3中，我们 将利用I型胶原特异性PET探测器，68GA-CBP8来确定EGCG在衰减中的影响 肺积累。 AIM 2和3的结果将提供有关剂量选择的关键信息。这 提案利用了一个多主体调查员团队的专业知识，该研究人员是纤维化生物学领域的领导者 临床试验设计，低成本干预和创新的分子探针。这些信息的总数 将提供设计II阶段所需的关键信息，其最终目标是开发急需的IPF 疗法。