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: 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
• 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' 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

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）：酒精性肝炎是一种肝脏炎症性疾病，在少数慢性酗酒者中发生，原因不明。炎症是肝损伤的根本原因，也是导致症状和死亡的原因。泼尼松龙是最常推荐的治疗方法，可提高大多数（但不是全部）患者的生存率。特别是，泼尼松龙不能改善 Lille 评分为 e0.45 的患者的生存率。为了提高酒精性肝炎的总体生存率，对未能缓解的患者需要新的治疗方法 泼尼松龙。我们建议评估两种药物治疗酒精性肝炎的效果。首先，我们将在患有以下疾病的患者中测试利洛西普，一种针对促炎细胞因子白介素-1 的药物 a 里尔评分 <0.45（对泼尼松龙有反应）。由于这些患者通过泼尼松龙治疗（标准护理治疗）获得了良好的生存率，因此我们将确定添加利洛那西普三周（利洛那西普+泼尼松龙）是否会导致血清胆红素（肝功能指标）更快改善。其次，我们将在 Lille 评分为 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 1 个月时死亡率为 25%（6 个月时死亡率为 75%），因此主要结果是与不治疗（标准护理）相比，接受泼尼松龙 + 麦考酚酯治疗的患者 28 天死亡率降低。使用泼尼松龙+霉酚酸酯旨在显着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有效的免疫抑制剂，因此将密切监测患者的感染情况，并将及时向数据安全监测委员会报告所有感染情况。该临床试验是大型转化研究项目的一部分，该项目将利用免疫组织学、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数据分析方法来研究肝脏炎症、肝细胞损伤和再生。这项临床试验和相关的转化项目将有助于更好地了解所涉及的炎症途径，并为酒精性肝炎的潜在新疗法提供数据 公共卫生相关性：对目前治疗严重急性酒精性肝炎的泼尼松龙有反应的患者 6 个月死亡率为 15%。不幸的是，35% 的患者对泼尼松龙没有反应，6 个月时死亡率为 75%。目前的临床试验将研究酒精性肝炎的新疗法，特别是对泼尼松龙无效的患者。