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

项目摘要/摘要 酒精性肝炎(AH)是与肝脏相关的发病率和死亡率的主要原因，显著缺乏 有效的治疗方法。F-652是一种IL-22激动剂，由于它的特性，有望成为治疗急性肝炎患者的药物。 抗氧化、抗凋亡、抗脂肪变性、抗微生物和促增殖作用 在各种实验系统中进行了演示。我们小组在急性肝炎患者中进行的一项初步研究证实 F-652的安全性和建议的有效性，没有令人担忧的药效学或药代动力学模式。 根据试点研究的令人鼓舞的结果，这项应用代表着下一步要确认 白介素22激动剂治疗急性肝炎的疗效观察这项建议的目的是：1.确定疗效和 在一项随机、安慰剂对照研究中证实IL-22激动剂(F-652)的安全性 90天时改善的MELD评分显示AH和MELD评分为11~20分。急性早幼粒细胞白血病患者 和MELD分数11-20(因此不是我们对RFA-AA-18-002的链接申请中描述的试验的候选者) 将接受1：1随机分为IL-22激动剂组或安慰剂(对照组)组。三剂IL-22 激动剂或安慰剂大约每隔5天给药一次。主要终点是改进 90天后MELD评分减少25%。次要终点包括30天和90天存活期；里尔 根据90天内无严重不良事件(SAE)来确定安全性。2.确定 在一项随机、安慰剂对照的研究中，IL-22激动剂(F-652)的有效性和安全性得到确认 90天时改善的MELD评分显示，AH和MELD评分为21-28分。 有激素禁忌症的急性肝炎患者(因此不是我们链接的试验的候选对象 应用于RFA-AA 18-002)和MELD评分21-28将经历2：1随机变成IL-22激动剂 手臂或安慰剂(对照)手臂。三剂IL-22激动剂或安慰剂将在 大约每隔5天。次要终点包括30天和90天的存活期；里尔评分；以及 由长达90天的SAE缺失期确定。我们认为试点随机对照试验是合乎逻辑的 扩展我们的初步研究，证明了IL-22激动剂的安全性和可能的有效性 急性加重期患者。调查人员处于独特的地位，可以执行拟议的研究，因为 与急性胰腺炎、临床试验指导和治疗发展相关的专业知识的广度和深度。

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.