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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

基本信息

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
项目类别：
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

项目摘要

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