Novel Therapies for Alcoholic Hepatitis with Sepsis and for Relapse Prevention

酒精性肝炎脓毒症和预防复发的新疗法

• 批准号: 10428495
• 负责人: ARUN J SANYAL
• 金额: $ 6.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428495
• 关键词: Acute; Addictive Behavior; Admission activity; Adverse event; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic Hepatitis; Antibiotics; Area; Ascorbic Acid; Back; Behavior; Behavioral; Bilirubin; Brain; Clinical; Clinical Trials; Critical Care; Data; Development; Dose; Enrollment; Environment; Family member; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Population; Goals; Hospitalization; Hour; Icterus; Impulsivity; Infection; Inflammation; Intravenous; Knowledge; Laboratories; Lead; Liver; Liver diseases; Magnetic Resonance Imaging; Measures; Morbidity - disease rate; Multiple Organ Failure; National Heart, Lung, and Blood Institute; National Institute of Drug Abuse; Oral cavity; Organ failure; Outcome; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Pilot Projects; Placebos; Population; Pre-Clinical Model; Questionnaires; Randomized; Recording of previous events; Recovery; Recurrence; Relapse; Research Personnel; Risk; Safety; Sepsis; Serum; Survivors; Testing; Therapeutic; TimeLine; Translating; Withdrawal; addiction; alcohol cue; alcohol testing; alcohol use disorder; base; cue reactivity; disorder later incidence prevention; drinking behavior; drug development; druggable target; effective therapy; improved; improved outcome; innovation; mortality; mortality risk; novel; novel therapeutics; predicting response; prevent; readmission rates; receptor; recidivism; response; response biomarker; systemic inflammatory response; virtual

Alcoholic Hepatitis (AH) is a major cause of liver-related morbidity and mortality. There are currently no approved therapies for severe AH. Two key barriers to drug development for severe AH are: (i) the high frequency of infection and sepsis which exclude most patients from clinical trials and is yet a major cause of mortality in this population, and (ii) the high rates of continued alcohol consumption after recovery from the acute illness that drives long-term mortality and re-hospitalization rates. In response to RFA-AA-18-005, we propose two pilot studies to begin to tackle these barriers. This will be accomplished by two sequentially performed trials as follows: Aim 1: To provide “proof of concept” that high-dose ascorbic acid (AscA) administered intravenously along with antibiotics to subjects with AH who have active infection and sepsis is well-tolerated, safe, reduces systemic inflammation and is potentially effective for the treatment of AH. This is based on strong preliminary data indicating that AscA reduces inflammation and progression to multi-organ dysfunction in those with severe sepsis. Given that AH is associated with severe inflammation, we will test the possibility that AscA may provide common therapy for both AH and sepsis. We will test a fixed dose established to be safe and potentially effective in severe sepsis, a comparably sick population to those with AH and sepsis to evaluate its safety, tolerability, ability to reduce systemic inflammation and to generate preliminary data on its ability to reduce progression to multi-organ failure, as assessed by a 2-point worsening of the SOFA score. These studies will innovate by repurposing AscA from its use in severe sepsis to AH with infection, a condition excluded from virtually all AH clinical trials. Aim 2: To provide “proof of concept” that lorcaserin, a 5HT2CR agonist, is well tolerated, reduces behavioral laboratory measured impulsivity, and enhances brain connectivity related to response inhibition and alcohol cue reactivity, and these changes correlate with reduction in alcohol use in survivors of AH. We will generate data on the safety, tolerability and efficacy of lorcaserin to reduce impulse control and related brain connectivity in those recovering from AH. We will also generate data on any effects of lorcaserin on alcohol consumption. This leverages our early data indicating that the 5HT2CR regulates impulsivity and associated alcohol consumption. Subjects recovering from a bout of AH requiring hospitalization will be enrolled 30-90 days after initial admission from AH. Thirty AH participants will be randomized to lorcaserin (10 mg twice a day by mouth) or placebo for four weeks. All participants will undergo two MR imaging sessions, one at baseline and one after four weeks of treatment with lorcaserin or placebo. Alcohol consumption will be measured at baseline, during treatment, and followed for one month after withdrawal from treatment to obtain preliminary data on effects of lorcaserin on alcohol consumption using alcohol timeline follow back questionnaires, serum phosphatidyl ethanol testing, and confirmation from family members. fMRI data will be related to alcohol consumption data. Trough levels of lorcaserin will be related to adverse events as well as alcohol consumption data.

酒精性肝炎(AH)是肝脏相关发病率和死亡率的主要原因。目前没有已批准的 重症急性胰腺炎的治疗。严重急性肝炎药物开发的两个关键障碍是：(I)高频率的 感染和败血症将大多数患者排除在临床试验之外，但仍是导致本病死亡的主要原因 人口，以及(2)从急性疾病康复后继续饮酒率高， 导致长期死亡率和再住院率。针对RFA-AA-18-005，我们建议两个试点项目 研究开始解决这些障碍。这将通过两个顺序执行的试验来完成，如下所示 目标1：提供大剂量抗坏血酸(ASCA)静脉注射的“概念证明” 与抗生素一起应用于有活动性感染和脓毒症的患者，耐受性良好，安全，减少 全身性炎症，对治疗急性肝炎有潜在的疗效。这是基于强劲的初步 数据表明，ASCA减少了炎症和进展为严重的多器官功能障碍 败血症。鉴于急性肝炎与严重炎症有关，我们将测试ASCA可能提供的 治疗急性胰腺炎和脓毒症的常用方法。我们将测试被确定为安全和潜在有效的固定剂量 在严重脓毒症中，将与AH和脓毒症患者相似的患病人群评估其安全性、耐受性、 能够减少全身性炎症，并产生关于其减少进展到 多器官衰竭，通过SOFA评分恶化2分来评估。这些研究将通过以下方式进行创新 将ASCA从用于严重脓毒症转变为AH合并感染，这是一种几乎所有AH都不存在的情况 临床试验。目标2：为5HT2CR激动剂氯卡斯林的耐受性好、降低 行为实验室测量了冲动，并增强了与反应抑制和 酒精提示反应性，这些变化与AH幸存者酒精使用量的减少有关。我们会 生成关于氯卡瑞林的安全性、耐受性和有效性的数据，以减少冲动控制和相关的大脑 从急性心肌梗塞中恢复的患者的连接性。我们还将生成有关氯酪蛋白对酒精的任何影响的数据 消费。这利用了我们早期的数据，该数据表明5HT2CR调节冲动性和相关 饮酒。从一轮需要住院的急性肝炎中恢复的受试者将被登记30-90天 从急诊室初次入院后。30名AH参与者将被随机给予氯卡韦林(每天两次，每次10毫克)。 口腔)或安慰剂，为期四周。所有参与者将接受两次磁共振成像，一次是基线，另一次是 在使用氯卡韦林或安慰剂治疗四周后一周。酒精消耗量将在基线上测量， 在治疗过程中，并在停药后随访一个月，以获得疗效的初步数据 用酒精时间线追踪氯酪蛋白对饮酒影响的问卷，血磷脂 酒精测试，以及家人的确认。FMRI数据将与酒精消费数据相关。 氯酪蛋白的低谷水平将与不良事件和酒精消费数据有关。