Randomized Placebo Controlled Pilot Trial to determine the efficacy of an IL22 agonist (F-652) in patients with Alcoholic Hepatitis

随机安慰剂对照预试验以确定 IL22 激动剂 (F-652) 对酒精性肝炎患者的疗效

• 批准号: 10202402
• 负责人: VIJAY H. SHAH
• 金额: $ 7.5万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202402
• 关键词: Adrenal Cortex Hormones; Agonist; Alcoholic Hepatitis; Antioxidants; Apoptotic; Cessation of life; Clinic; Clinical Research; Conduct Clinical Trials; Data; Development; Disease; Dose; Drug Kinetics; Environment; Future; Group Practice; Investigation; Link; Liver; Morbidity - disease rate; Patient Recruitments; Patients; Pattern; Pentoxifylline; Pharmacodynamics; Phase; Pilot Projects; Placebo Control; Placebos; Positioning Attribute; Prednisone; Randomized; Randomized Controlled Trials; Research; Research Personnel; Safety; Serious Adverse Event; Signal Transduction; Steroids; System; Testing; antimicrobial; arm; base; clinical investigation; drug efficacy; follow-up; improved; innovation; interleukin-22; liver cell proliferation; liver transplantation; mortality; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 3 study; pilot trial; primary endpoint; randomized placebo controlled study; secondary endpoint; success; therapeutic development; therapeutically effective

PROJECT SUMMARY/ABSTRACT Alcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity of effective therapeutics. F-652, an IL-22 agonist, is a promising agent to treat patients with AH because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and pro-proliferative effects that have been demonstrated in various experimental systems. A pilot study from our group in patients with AH has confirmed safety and suggested efficacy of F-652, with no worrisome pharmacodynamic or pharmacokinetic patterns. Based on the encouraging results from the pilot study, this application represents the next step to confirm efficacy of the IL-22 agonist in patients with AH. The aims of this proposal are: 1. Determine the efficacy and confirm the safety of an IL-22 agonist (F-652) in a randomized, placebo-controlled study in patients with AH and MELD score 11-20 as demonstrated by improved MELD scores at 90 days. Patients with AH and MELD score 11-20 (thus not candidates for the trial described in our linked application to RFA-AA-18-002) will undergo a 1:1 randomization into an IL-22 agonist arm or a placebo (control) arm. Three doses of the IL-22 agonist or placebo will be administered at approximately 5-day intervals. The primary endpoint is improvement (reduction) in MELD score by >25% at 90 days. Secondary endpoints include 30- and 90-day survival; Lille score; and safety as determined by absence of serious adverse events (SAE) at 90 days. 2. Determine the efficacy and confirm the safety of an IL-22 agonist (F-652) in a randomized, placebo-controlled study in patients with AH and MELD score 21-28 as demonstrated by improved MELD scores at 90 days. Patients with AH with contraindication to steroids (thus not candidates for the trial described in our linked application to RFA-AA 18-002) and MELD score 21-28 will undergo a 2:1 randomization into an IL-22 agonist arm or a placebo (control) arm. Three doses of the IL-22 agonist or placebo will be administered at approximately 5-day intervals. Secondary endpoints include 30- and 90-day survival; Lille score; and safety as determined by absence of SAE up to 90 days. We believe a pilot randomized controlled trial is a logical extension of our preliminary studies which demonstrated safety and possible efficacy of the IL-22 agonist in patients with AH. The investigators are uniquely positioned to perform the proposed study given substantial breadth and depth of expertise related to AH, clinical trial conduct, and therapeutic development.

项目摘要/摘要 酒精性肝炎（AH）是肝脏相关发病率和死亡率的主要原因， 有效的治疗方法。F-652，一种IL-22激动剂，是一种有希望的治疗AH患者的药物，因为其 抗氧化、抗凋亡、抗脂肪变性、抗微生物和促增殖作用， 在不同的实验系统中得到验证。我们小组在AH患者中进行的一项初步研究证实， F-652的安全性和建议疗效，没有令人担忧的药效学或药代动力学模式。 基于试点研究的令人鼓舞的结果，该应用程序代表了下一步确认 IL-22激动剂在AH患者中的疗效。本提案的目的是：1.确定疗效， 在一项随机、安慰剂对照研究中证实了IL-22激动剂（F-652）的安全性 AH和MELD评分为11-20，如90天时MELD评分改善所证明。AH患者 和MELD评分11-20（因此不是我们与RFA-AA-18-002相关的申请中所述试验的候选人） 将进行1：1随机化至IL-22激动剂组或安慰剂（对照）组。 激动剂或安慰剂将以大约5天的间隔施用。主要终点是改善 在90天时，MELD评分降低>25%。次要终点包括30天和90天生存期;里尔 评分;以及通过在90天时不存在严重不良事件（SAE）确定的安全性。2.确定 在一项随机、安慰剂对照研究中， AH和MELD评分21-28的患者，如90天时MELD评分改善所证明的。 有类固醇禁忌症的AH患者（因此不是我们的链接中描述的试验的候选人） 应用于RFA-AA 18-002）和MELD评分21-28的受试者将以2：1随机化至IL-22激动剂中 三个剂量的IL-22激动剂或安慰剂将在10天内施用。 大约5天的间隔。次要终点包括30天和90天生存期、里尔评分和安全性， 根据90天内无SAE确定。我们相信一个试点随机对照试验是一个合乎逻辑的 我们的初步研究的扩展，这些研究证明了IL-22激动剂在以下方面的安全性和可能的疗效： AH患者。研究者处于独特的地位，可以进行拟议的研究， 与AH、临床试验实施和治疗开发相关的专业知识的广度和深度。