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）是与肝有关的发病率和死亡率的主要原因，显着匮乏 有效的治疗学。 F-652是IL-22激动剂，是一种有前途的药物，可以治疗AH患者 抗氧化剂，抗凋亡，抗溶裂性，抗微生物和促增殖作用已 在各种实验系统中证明。我们小组对AH患者的一项试点研究已证实 安全性和建议的F-652功效，没有令人担忧的药效或药代动力学模式。 基于试点研究的令人鼓舞的结果，该应用代表下一步确认 IL-22激动剂在AH患者中的功效。该提案的目的是：1。确定功效和 在一项随机的安慰剂对照研究中，确认IL-22激动剂（F-652）的安全性 AH和MELD得分为11-20，如90天时的MELD分数​​提高所证明。 AH患者 和MELD得分为11-20（因此不是我们链接到RFA-AA-18-002中所述的试验的候选者） 将在IL-22激动臂或安慰剂（控制）臂中进行1：1随机分组。三剂IL-22 激动剂或安慰剂将以大约5天的间隔进行管理。主要终点是改进 （降低）在90天内将MELD评分> 25％。次要终点包括30天和90天的生存；里尔 分数;和安全性由90天后没有严重的不良事件（SAE）确定。 2。确定 在一项随机的安慰剂控制研究中，有效并确认IL-22激动剂（F-652）的安全性 AH和MELD的患者得分为21-28，如90天时的MELD分数​​提高所证明。 AH患有类固醇禁忌症的患者（因此不是我们链接的试验的候选者 申请RFA-AA 18-002）和MELD得分21-28将在IL-22激动剂中进行2：1随机分组 手臂或安慰剂（控制）手臂。三剂IL-22激动剂或安慰剂将在 大约5天的间隔。次要终点包括30天和90天的生存；里尔得分；和安全 由最多90天的SAE确定。我们认为飞行员随机对照试验是合乎逻辑的 我们的初步研究的扩展，该研究证明了IL-22激动剂在 AH患者。研究人员的独特位置可以执行拟议的研究，鉴于大量 与AH，临床试验行为和治疗发展有关的专业知识的广度和深度。