Collaborative Clinical Research on Hepatotoxicity

肝毒性合作临床研究

• 批准号: 8626897
• 负责人: NAGA P CHALASANI
• 金额: $ 28.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626897
• 关键词: Acute; Address; Adult; Ambulatory Care Facilities; Ancillary Study; Antigens; Attenuated; Autoantibodies; Autoantigens; Autoimmune Hepatitis; Autoimmune Process; Biological Assay; Biological Markers; Budesonide; Case-Control Studies; Cessation of life; Child; Childhood; Clinical; Clinical Research; County Hospitals; Data Coordinating Center; Diagnosis; Diagnostic; Double-Blind Method; Eligibility Determination; Enrollment; Epidemiology; Etiology; Exclusion; Exhibits; Funding; Gastroenterology; Glucocorticoids; Goals; Health; Healthcare; Hepatotoxicity; Hospitals; Indiana; Individual; Institutes; Knowledge; Lead; Liver Failure; Medical Informatics; Morbidity - disease rate; Multicenter Studies; Natural History; Oral; Outcome; Pathogenesis; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phenotype; Pilot Projects; Placebo Control; Placebos; Prospective Studies; Proteomics; Publishing; Qualifying; Randomized; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Retrospective Studies; Risk Factors; Safety; Serious Adverse Event; Severities; Site; Source; Steroids; Testing; Therapeutic; Therapeutic Human Experimentation; Transplantation; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; acute drug induced liver toxicity; chronic liver disease; clinical Diagnosis; improved; liver injury; meetings; member; mortality; non-drug; novel; operation; prospective; public health relevance; response; tertiary care; total measurement Bilirubin

DESCRIPTION (provided by applicant): This application is submitted in response to RFA DK-13-003 which solicits applications from qualified investigators for the continuation of the Drug Induced Liver Injury Network (DILIN). Indiana University is one of the five founding clinical centers and has robustly participated in all DILIN operations since its inception. We propose the following specific aims to meet the goals of this RFA. Specific Aim # 1: To enroll large number of eligible adults with suspected DILI into ongoing DILIN studies. We propose to collect prospective cases of suspected DILI from multiple sources in Central Indiana, each providing distinctive epidemiological facets and research potential. Specific Aim # 2: To enroll significant number of eligible children with suspected DILI into ongoing DILIN studies. We propose to include Cincinnati Children's Hospital as a satellite site to significantly increase the number of children enrolled into ongoing DILIN studies. Specific Aim # 3: The DILI is currently a diagnosis of exclusion and it can be a challenging diagnosis to make. We propose to conduct two ancillary studies in order to develop tests that facilitate the diagnosis of DILI: (i) we will conduct a discovery proteomic study of individuals with acute liver injury due to DILI and non-DILI etiologies enrolled within two weeks of liver injury onset to identify biomarkers specific for acut liver injury due to DILI; (ii) DILI can sometime mimic autoimmune hepatitis and it is difficult to distinguish it from de novo autoimmune hepatitis. To address this clinical conundrum, we will conduct a preliminary study for autoantibody profiling using an auto-antigen array assay among individuals with (i) acute DILI with autoimmune hepatitis-like features, (ii) acute DILI without autoimmune hepatitis features, and (iii) acute autoimmune hepatitis without precedent medication exposure. Specific Aim # 4: DILI carries considerable mortality and morbidity but there is no treatment available other than withdrawing the offending agent. In order to address this unmet therapeutic need, we propose to conduct a randomized, double-blind, placebo-controlled pilot study of budesonide in individuals with well characterized hepatocellular DILI meeting predefined eligibility criteria. Our hypothesis is that oral budesonide, a steroid with hig glucocorticoid activity and substantial first pass elimination, attenuates liver injury and improve outcomes of patients with hepatocellular DILI.

描述（由申请人提供）：本申请是为了回应RFA DK-13-003而提交的，RFA DK-13-003征求合格研究者继续药物性肝损伤网络（DILIN）的申请。印第安纳州大学是五个创始临床中心之一，并已在所有DILIN业务自成立以来，有力地参与。我们提出以下具体目标，以实现本RFA的目标。具体目标1：将大量符合条件的疑似DILI成人入组正在进行的DILIN研究。我们建议从印第安纳州中部的多个来源收集疑似DILI的前瞻性病例，每个来源提供独特的流行病学方面和研究潜力。具体目标#2：将大量符合条件的疑似DILI儿童纳入正在进行的DILIN研究。我们建议将辛辛那提儿童医院作为卫星中心，以显著增加正在进行的DILIN研究中入组的儿童数量。具体目标#3：DILI目前是一种排除性诊断，可能是一种具有挑战性的诊断。我们建议进行两项辅助研究，以开发有助于诊断DILI的检测方法：（i）我们将对肝损伤发作后两周内招募的因DILI和非DILI病因引起的急性肝损伤个体进行发现蛋白质组学研究，以鉴定特异性针对DILI引起的急性肝损伤的生物标志物;（ii）DILI有时可以模拟自身免疫性肝炎，并且难以将其与新生自身免疫性肝炎区分开。为了解决这一临床难题，我们将在患有（i）急性DILI伴自身免疫性肝炎样特征、（ii）急性DILI不伴自身免疫性肝炎特征和（iii）急性自身免疫性肝炎无既往药物暴露的个体中，使用自身抗原阵列试验进行自身抗体谱分析的初步研究。具体目标#4：DILI具有相当高的死亡率和发病率，但除了停用致病药物外，没有其他治疗方法。为了解决这一未满足的治疗需求，我们建议在符合预定合格标准的肝细胞DILI患者中进行一项布地奈德的随机、双盲、安慰剂对照初步研究。我们的假设是口服布地奈德，一种具有高糖皮质激素活性和大量首过消除的类固醇，减轻肝损伤并改善肝细胞DILI患者的预后。