Epigallocatechin gallate for prevention of lethal cirrhosis complications

表没食子儿茶素没食子酸酯用于预防致命性肝硬化并发症

• 批准号: 10713745
• 负责人: Yujin Hoshida
• 金额: $ 68.45万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713745
• 关键词: Acoustics; Adverse event; Biological Markers; Cause of Death; Chemoprevention; Chemopreventive Agent; Cirrhosis; Clinical; Clinical Chemoprevention; Clinical Trials; Conduct Clinical Trials; Consent; Controlled Clinical Trials; Development; Double-Blind Method; Epigallocatechin Gallate; Future; Goals; Green tea; Hepatic; Histologic; Immunohistochemistry; Incidence; Individual; Liver; Lung; Malignant Neoplasms; Measurement; Measures; Mediating; Medical; Molecular; Molecular Target; Monitor; Myofibroblast; Oral Administration; Participant; Patient Selection; Patient-Focused Outcomes; Patients; Phase; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Prevention; Primary carcinoma of the liver cells; Quality of life; Randomized; Research Design; Risk; Rodent Model; Safety; Sample Size; Sampling; Serum; Slice; Stromal Cells; Surrogate Endpoint; Testing; Therapeutic; Time; Tissues; cell type; clinical translation; clinically relevant; design; dietary supplements; elastography; experimental study; follow-up; high risk; improved; indexing; insight; liver biopsy; liver stiffness; mortality; novel; patient prognosis; patient subsets; permissiveness; phase I trial; phase III trial; prevent; prevention clinical trial; primary endpoint; prognostic; response; secondary endpoint; senescence; translational approach; translational therapeutics; tumor

Summary Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, and the fastest rising cancer mortality in the U.S. Due to the limited efficacy of existing therapies for established HCC tumors, prognosis for patients remains poor, with five-year survival under 15%. Thus, HCC chemoprevention in cirrhosis is likely the most impactful strategy to improve survival. However, despite the candidate chemopreventive agents suggested in experimental studies, it remains an unmet need due to logistical difficulty in conducting clinical trials that require large sample size and long follow-up time. To overcome the challenge, we identified Prognostic Liver Secretome signature (PLSec) to quantitatively monitor therapeutic modulation of HCC risk level in cirrhosis patients, and predict reduction of future incident HCC. PLSec has been used as a surrogate endpoint in our ongoing and planned HCC chemoprevention clinical trials. Experimental studies in rodent models by us and others suggested that epigallocatechin gallate (EGCG), a green tea catechin, prevents HCC development without any adverse events. Our ex vivo organotypic culture of precision-cut liver slice (PCLS) from cirrhosis patients revealed suppression of high-risk signature by EGCG, supporting its clinical relevance. Based on these promising findings, the goal of our proposal is to test our hypothesis that EGCG treatment safely suppresses PLSec in patients with cirrhosis. Aim 1. Evaluate safety and efficacy of EGCG in cirrhosis patients (phase II double-blinded placebo-controlled clinical trial). We will evaluate 24-week EGCG treatment or placebo in 60 patients (1:1 randomization) with early-stage cirrhosis enriched for elevated HCC risk by a clinical variable-based score (FIB-4 index) and PLSec. Participants will be monitored monthly for adverse events. Serum samples will be obtained before, during, and at the end of treatment. Primary endpoint: reduction of risk level as measured by PLSec (delta-PLSec). Secondary endpoints: safety profile, change in quality of life. Exploratory endpoints: change in on-treatment PLSec, immunohistochemistry of HCC-risk-related markers for participants consented for liver biopsy, and incident HCC. Aim 2. Identify factors associated with response to EGCG in cirrhosis patients. We will evaluate pre-treatment PLSec and clinico-histological variables; on-treatment PLSec modulation and plasma concentration of EGCG and its metabolites for their association with the primary endpoint. We will also assess modulation of the FIB-4 index and liver stiffness measurement by acoustic elastography as potential alternative clinical endpoints to monitor effect of EGCG, We expect to establish novel HCC chemoprevention with a dietary supplement for subsequent pivotal phase III clinical trial toward clinical translation of this approach, which will contribute to a transformative improvement in the outcome of patients with HCC by enabling individual- risk-based, molecular-targeted, and safe chemoprevention of this deadly cancer.

概括 肝细胞癌（HCC）是肝硬化患者死亡的主要原因，也是最快上升的原因 由于现有疗法对既定的HCC肿瘤的疗效有限，美国的癌症死亡率有限， 患者的预后仍然很差，五年生存率低于15％。因此，肝硬化中的HCC化学预防 可能是改善生存的最有影响力的策略。但是，尽管候选化学预防剂 在实验研究中建议，由于进行临床试验的后勤困难，这仍然是未满足的需求 这需要大量样本量和较长的随访时间。为了克服挑战，我们确定了预后肝 分泌组签名（PLSEC）用于定量监测肝硬化中HCC风险水平的治疗调制 患者，并预测减少未来事件HCC。 PLSEC已被用作我们的替代端点 正在进行的HCC化学预防临床试验。我们和啮齿动物模型中的实验研究 其他人则建议绿茶儿茶素的Epigallocatechin Gallate（EGCG）可防止HCC开发 没有任何不利事件。我们从肝硬化的精确切割肝切片（PCL）的离体器官型培养 患者显示EGCG抑制高风险签名，支持其临床相关性。基于这些 有希望的发现，我们提案的目的是检验我们的假设，即EGCG治疗安全抑制 肝硬化患者的PLSEC。 AIM 1。评估EGCG在肝硬化患者中的安全性和功效（II期 双盲安慰剂对照临床试验）。我们将评估60的24周EGCG治疗或安慰剂 患者（1：1随机化）患有早期肝硬化的患者富含临床可变的HCC风险升高 得分（FIB-4索引）和PLSEC。参与者将每月监视不良事件。血清样品会 可以在治疗之前，期间和结束时获得。主要终点：降低风险水平 由PLSEC（Delta-Plsec）。次要终点：安全性，生活质量的变化。探索性终点： 更改治疗PLSEC，与参与者同意的HCC风险相关标记的免疫组织化学 用于肝活检和事件HCC。目标2。确定与肝硬化患者中对EGCG反应有关的因素。 我们将评估治疗前的PLSEC和临床 - 历史变量；治疗PLSEC调制和 EGCG的血浆浓度及其与主要终点相关的代谢产物。我们也会 评估通过声学弹性图的FIB-4指数和肝脏刚度测量的调制为潜在 替代临床终点以监测EGCG的效果，我们希望建立新型的HCC化学预防 通过饮食补充剂，用于随后的关键阶段III期临床试验，用于这种方法的临床翻译， 这将通过实现个体，可以改善HCC患者的结果 这种致命的癌症基于风险的，靶向分子和安全的化学预防。