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。目前没有批准 严重AH的治疗方法。严重AH药物开发的两个关键障碍是：（i）高频率的 感染和脓毒症将大多数患者排除在临床试验之外，但仍是本研究中死亡的主要原因。 （二）从急性疾病中恢复后继续饮酒的高比率， 导致长期死亡率和再住院率。作为对RFA-AA-18-005的回应，我们提出了两个试点 研究开始来解决这些障碍。这将通过两个连续进行的试验来完成， 目的1：提供静脉注射高剂量抗坏血酸（AscA）的“概念证明” 沿着抗生素治疗具有活动性感染和脓毒症的AH受试者耐受性良好，安全， 全身性炎症，并可能有效治疗AH。这是基于强大的初步 有数据表明，AscA可减少炎症，并可减少严重肝硬化患者多器官功能障碍的进展。 败血症鉴于AH与严重炎症有关，我们将测试AscA可能提供的可能性。 AH和脓毒症的常见治疗。我们将测试确定安全且潜在有效的固定剂量 在严重脓毒症中，将一组患者与AH和脓毒症患者进行比较，以评价其安全性、耐受性 减少全身炎症的能力，并生成关于其减少进展至 多器官衰竭，通过SOFA评分恶化2分进行评估。这些研究将创新， 将AscA从用于严重脓毒症改为AH伴感染，这是一种几乎被所有AH排除的疾病 临床试验目的2：提供“概念验证”，证明氯卡色林（一种5 HT 2CR激动剂）耐受良好， 行为实验室测量冲动，并增强与反应抑制相关的大脑连接， 酒精提示反应性，这些变化与AH幸存者中酒精使用的减少相关。我们将 生成关于氯卡色林减少冲动控制和相关脑损伤的安全性、耐受性和疗效的数据 从AH中恢复的人的连接。我们还将生成氯卡色林对酒精的任何影响的数据 消费这利用了我们早期的数据，表明5 HT 2CR调节冲动和相关的 酒精消费。从需要住院治疗的AH发作中恢复的受试者将入组30-90天 从AH初次入院后。30名AH受试者将随机接受氯卡色林（10 mg，每日两次， 口）或安慰剂四周。所有参与者将接受两次MR成像，一次在基线， 用氯卡色林或安慰剂治疗四周后一次。将在基线时测量酒精消耗量， 在治疗期间，并在停止治疗后随访一个月，以获得有关影响的初步数据 使用酒精时间轴随访问卷，血清磷脂酰 酒精测试和家属的确认fMRI数据将与饮酒数据相关。 氯卡色林的谷水平将与不良事件以及饮酒数据相关。