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

• 批准号: 8914475
• 负责人: TIMOTHY ROSS MORGAN
• 金额: $ 67.75万
• 依托单位: SOUTHERN CALIFORNIA INST FOR RES/EDUC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914475
• 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' s disease; Data; Data Analyses; Disease; 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

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

描述（由申请人提供）：酒精性肝炎是一种肝脏炎症性疾病，发生在少数慢性酒精中毒者中，原因不明。炎症是肝损伤的根本原因，也是症状和死亡的原因。泼尼松龙是最常推荐的治疗方法，可改善大多数（但不是所有）患者的生存率。特别是，泼尼松龙不能改善里尔评分e0.45的患者的生存率。为了提高酒精性肝炎的总生存率，需要对无效患者进行新的治疗 强的松龙我们建议评价两种药物在酒精性肝炎。首先，我们将测试利洛那塞，一种针对促炎细胞因子白细胞介素-1的药物， a里尔评分<0.45（泼尼松龙应答者）。由于这些患者在泼尼松龙治疗（标准治疗）下具有极好的存活率，我们将确定添加利洛那塞三周（利洛那塞+泼尼松龙）是否会导致血清胆红素（肝功能的测量）更快的改善。其次，我们将在里尔评分e0.45的患者中测试霉酚酸酯，一种针对淋巴细胞的药物。由于这些患者在1个月时的死亡率为25%（6个月时的死亡率为75%），因此主要结局将是接受泼尼松龙+霉酚酸酯治疗的患者与未接受治疗的患者相比28天死亡率降低（标准治疗）。泼尼松龙+霉酚酸酯的使用旨在显著减少对泼尼松龙无反应的患者的肝脏炎症。由于泼尼松龙+麦考酚酯的组合是一种强效免疫抑制剂，因此将密切监测患者的感染情况，并将所有感染及时报告给数据安全监测委员会。这项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、外周血免疫学研究、肝脏转录组学、肝脏蛋白质组学和系统生物学方法进行数据分析，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导致更好地了解所涉及的炎症途径，并为酒精性肝炎的潜在新治疗方法提供数据