A prospective, randomized, clinical trial to evaluate two novel therapies, mycoph

一项评估两种新疗法 mycoph 的前瞻性随机临床试验

基本信息

批准号：
8428900
负责人：
TIMOTHY ROSS MORGAN
金额：
$ 72.48万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8428900
关键词：
Acute Alcoholic Hepatitis Adverse event Age Albumins Alcoholic Hepatitis Bilirubin Blood specimen Cessation of life Chronic Clinical Clinical Trials Clinical Trials Data Monitoring Committees Creatinine Crohn&apos s disease Data Data Analyses Disease Health Hepatic Immunologics Immunosuppressive Agents Infection Inflammation Inflammatory Injury Interleukin-1 Lead Liver Liver diseases Lymphocyte Lymphocyte Function Macrophage Activation Measures Minority Monitor Mycophenolate Natural regeneration Oral Outcome Pathway interactions Patients Pharmaceutical Preparations Proteomics Psoriasis Randomized Clinical Trials Reporting Research Project Grants Rheumatoid Arthritis Serum Steroids Symptoms Syndrome Systems Biology Testing Translational Research cytokine design effective therapy efficacy testing improved liver function liver inflammation liver injury mortality mycophenolate mofetil novel peripheral blood prednisolone primary outcome problem drinker prospective response secondary outcome standard of care transcriptomics treatment duration

项目摘要

DESCRIPTION (provided by applicant): Alcoholic hepatitis is an inflammatory disease of the liver that occurs for unknown reasons in a minority of chronic alcoholics. Inflammation is the underlying cause of liver injury and the cause of symptoms and death. Prednisolone, the most commonly recommend treatment, improves survival in most, but not all, patients. In particular, prednisolone does not improve survival among patients with a Lille score e0.45. To improve overall survival in alcoholic hepatitis, new treatments are needed for patients who fail to respond to prednisolone. We propose to evaluate two drugs in alcoholic hepatitis. First, we will test rilonacept, a drug directed against the pro- inflammatory cytokine, interleukin-1, in patients with a Lille score <0.45 (responders to prednisolone). Because these patients have an excellent survival with prednisolone treatment (standard of care treatment), we will determine whether the addition of rilonacept for three weeks (rilonacept+prednisolone) will result in a more rapid improvement in serum bilirubin (a measure of liver function). Second, we will test the mycophenolate, a drug directed against lymphocytes, among patients with a Lille score e0.45. Because these patients have a 25% mortality at 1 month (and 75% mortality at 6 months), the primary outcome will be a reduction in 28-day mortality among patients receiving prednisolone+mycophenolate as compared with no treatment (standard of care). Use of a prednisolone+mycophenolate is designed to markedly reduce hepatic inflammation in patients who do not respond to prednisolone. Because the combination of prednisolone+mycophenolate is a potent immunosuppressant, patients will be monitored closely for infection and all infections will be reported promptly to a Data Safety Monitoring Board. This clinical trial is a component of a large, translational research project that will investigate liver inflammation, hepatocellular injury and regeneration using immunohistology, immunologic studies of peripheral blood, liver transcriptomics, liver proteomics and a systems biology approach to data analysis. This clinical trial and the associated translational projects will lead to a better understanding of the inflammatory pathways involved and provide data for potential new treatments for alcoholic hepatitis PUBLIC HEALTH RELEVANCE: Patients who respond to prednisolone, the current treatment for severe acute alcoholic hepatitis, have a 15% mortality at 6-months. Unfortunately, 35% of patients fail to respond to prednisolone and have a 75% mortality at 6 months. The current clinical trial will investigate new treatments for alcoholic hepatitis, especially among patients wo fail to respond to prednisolone.

描述（由申请人提供）：酒精性肝炎是肝脏的炎症性疾病，出于少数慢性酒精中毒的原因而发生。炎症是肝损伤的根本原因以及症状和死亡的原因。泼尼松龙是最常见的治疗方法，可改善大多数但不是全部患者的生存率。特别是，泼尼松龙不能改善Lille评分E0.45的患者的生存率。为了改善酒精性肝炎的总体生存，需要新的治疗方法到泼尼松龙。我们建议评估酒精性肝炎中的两种药物。首先，我们将测试针对促炎性细胞因子介体的药物介体的药物，介绍里尔评分<0.45（泼尼松龙的响应者）。由于这些患者在泼尼松龙治疗（护理标准治疗）方面具有出色的生存期，因此我们将确定三周内添加Rilonacept（Rilonacept+泼尼松龙）是否会导致血清胆红素（肝功能量度）的更快改善。其次，我们将在Lille评分E0.45的患者中测试一种针对淋巴细胞的药物（一种针对淋巴细胞的药物）。由于这些患者在1个月时死亡率为25％（在6个月时死亡率为75％），因此与无治疗相比，接受泼尼松龙+霉酚酸酯的患者的28天死亡率将降低28天的死亡率（标准护理）。泼尼松龙+霉酚酸盐的使用旨在显着减少对泼尼松龙反应的患者的肝炎。由于泼尼松龙+霉酚酸盐的组合是一种有效的免疫抑制剂，因此将密切监测患者以感染，并将迅速报告给数据安全监测板。该临床试验是一个大型转化研究项目的组成部分，该项目将使用免疫组织学，外周血，肝脏转录组学，肝蛋白质组学和系统生物学方法进行数据分析研究，研究肝脏炎症，肝细胞损伤和再生。这项临床试验和相关的翻译项目将使人们对所涉及的炎症途径有更好的了解，并为酒精性肝炎的潜在治疗方法提供数据公共卫生相关性：对泼尼松龙的反应的患者（当前严重急性酒精性肝炎的治疗方法）在6个月时死亡15％。不幸的是，35％的患者未能对泼尼松龙反应，在6个月时死亡率为75％。当前的临床试验将调查酒精性肝炎的新治疗方法，尤其是在患者中，未能对泼尼松龙反应。