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

描述(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患者身上，原因不明。炎症是肝脏损伤的根本原因，也是症状和死亡的原因。泼尼松龙是最常用的治疗方法，可提高大多数但不是所有患者的存活率。特别是，强的松龙不能改善Lille评分为0.45的患者的存活率。为了提高酒精性肝炎的总体存活率，需要对无反应的患者进行新的治疗 强的松龙。我们建议对两种治疗酒精性肝炎的药物进行评估。首先，我们将测试利洛那普，一种针对促炎细胞因子白介素1的药物，在慢性阻塞性肺疾病患者中。 里尔评分0.45(对强的松龙有效)。由于这些患者在接受强的松龙治疗(标准护理治疗)后存活率很高，我们将确定加用利洛那塞普三周(利洛奈普+强的松龙)是否会更快地改善血清胆红素(肝功能的一项指标)。其次，我们将在里尔评分为0.45的患者中测试霉酚酸酯，这是一种针对淋巴细胞的药物。由于这些患者1个月的死亡率为25%(6个月的死亡率为75%)，与不接受治疗(标准护理)相比，接受强的松龙+霉酚酸酯治疗的患者的28天死亡率将降低。强的松龙+霉酚酸酯的使用被设计为显著减少对强的松龙无效的患者的肝脏炎症。由于强的松龙+霉酚酸酯的组合是一种有效的免疫抑制剂，患者将受到密切监测，所有感染都将迅速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性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翻译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：对目前治疗重症急性酒精性肝炎的强的松龙有反应的患者，6个月后的死亡率为15%。不幸的是，35%的患者对强的松龙无效，6个月后死亡率为75%。目前的临床试验将研究治疗酒精性肝炎的新方法，特别是对强的松龙无效的患者。

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.