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。目前还没有获批的 严重 AH 的治疗。严重 AH 药物开发的两个主要障碍是：(i) 感染和败血症将大多数患者排除在临床试验之外，并且仍然是该领域死亡的主要原因 人口，以及（ii）从急性疾病康复后继续饮酒的比例很高， 推动长期死亡率和再住院率。为了回应 RFA-AA-18-005，我们提议两个试点 研究开始解决这些障碍。这将通过两个连续进行的试验来完成 目标 1：提供静脉注射高剂量抗坏血酸 (AscA) 的“概念证明” 与抗生素一起用于患有活动性感染和败血症的 AH 受试者耐受性良好、安全，可减少 全身性炎症，对治疗 AH 具有潜在效果。这是基于强有力的初步 数据表明，AscA 可以减少患有严重疾病的患者的炎症和多器官功能障碍的进展 败血症。鉴于 AH 与严重炎症相关，我们将测试 AscA 可能提供的可能性 AH 和脓毒症的常见治疗方法。我们将测试确定的固定剂量是否安全且可能有效 在严重脓毒症中，与患有 AH 和脓毒症的患者相比，评估其安全性、耐受性、 能够减少全身炎症并生成有关其减少进展的能力的初步数据 多器官衰竭，通过 SOFA 评分恶化 2 分来评估。这些研究将通过创新 将 AscA 从用于严重败血症改为 AH 感染，这种情况几乎排除在所有 AH 之外 临床试验。目标 2：提供“概念证明”，证明 5HT2CR 激动剂氯卡色林具有良好的耐受性，可减少 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 幸存者饮酒的减少相关。我们将 生成有关氯卡色林减少冲动控制和相关大脑的安全性、耐受性和有效性的数据 从 AH 中恢复的人的连接性。我们还将生成有关氯卡色林对酒精影响的数据 消耗。这利用了我们的早期数据，表明 5HT2CR 调节冲动和相关的 饮酒量。从需要住院治疗的 AH 中恢复的受试者将在 30-90 天后入组 从 AH 初次入学后。三十名 AH 参与者将被随机分配到氯卡色林（10 毫克，每天两次） 口）或安慰剂四个星期。所有参与者将接受两次 MR 成像，一次是基线，一次是 氯卡色林或安慰剂治疗四周后一次。酒精消耗量将在基线时进行测量， 治疗期间，停药后随访1个月，以获得初步效果数据 使用酒精时间线跟踪问卷、血清磷脂酰来评估氯卡色林对饮酒的影响 乙醇测试​​，并得到家庭成员的确认。功能磁共振成像数据将与饮酒数据相关。 氯卡色林的谷值与不良事件以及饮酒数据有关。