ILIAD

伊利亚德

• 批准号: 7607620
• 负责人: HERBERT L BONKOVSKY
• 金额: $ 0.03万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7607620
• 关键词: Alanine Transaminase; Amoxicillin-Potassium Clavulanate Combination; Authorization documentation; Biological; Biological Specimen Banks; Blood; Blood specimen; Case Report Form; Causations; Cells; Characteristics; Clinical; Clinical Data; Compatible; Computer Retrieval of Information on Scientific Projects Database; Consent; Consent Forms; DNA; Databases; Diabetes Mellitus; Drug Delivery Systems; Enrollment; Etiology; Event; Excision; Failure; Freezing; Funding; Future; Gastroenterologist; Genomics; Goals; Grant; Health Insurance Portability and Accountability Act; Health Personnel; Health Professional; Hospitalization; Immune; Individual; Informed Consent; Injury; Institutes; Institution; International Normalized Ratio; Interview; Investigation; Kidney Diseases; Life; Liver; Liver Dysfunction; Lymphocyte; Mails; Marketing; Medical; Medical Records; Morbidity - disease rate; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phenytoin; Physicians; Plasma; Population; Predisposition; Procedures; Protocols documentation; Purpose; Rate; Recontacts; Registries; Research; Research Design; Research Personnel; Resources; Serum; Shipping; Ships; Source; Specimen; Study Subject; Telephone; Time; United States National Institutes of Health; Universities; Upper Limit of Normal; Valproic Acid; abstracting; base; clinical research site; drug mechanism; experience; follow-up; interest; isoniazid; liver biopsy; mortality; patient registry; repository; total measurement Bilirubin

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale: Drug induced liver injury (DILI) is the single most common reason for regulatory actions concerning drugs, including failure to gain approval for marketing, removal from the market place, and restriction of prescribing indications. DILI is also a significant cause of morbidity and mortality in many patient populations. To stimulate and facilitate research into DILI, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) has recently established the Drug-Induced Liver Injury Network (DILIN). One of the initial projects to be conducted by the network is to retrospectively establish a nationwide registry of patients who have suffered severe idiosyncratic liver injury associated with drugs (ILIAD), and to collect, immortalize and store serum, Deoxyribonucleic acid (DNA), and lymphocytes from these patients (hereafter referred to as the "ILIAD protocol"). This ILIAD protocol will serve as a resource for subsequent mechanistic investigations of the basis for susceptibility to severe idiosyncratic DILI. Specific Aims and Objectives: The primary goal of the ILIAD protocol is to create: (a) a clinical database consisting of individuals who have experienced severe DILI caused by four specific drugs, and the relevant clinical data concerning the episode of DILI; and, (b) to create a bank of biological specimens obtained from these individuals. Corresponding information from control subjects will also be collected. These biological specimens will be DNA, plasma, and immortalized lymphocytes. Immortalized lymphocytes will provide unlimited amounts of genomic DNA for study as well as living immune cells for phenotyping studies. A secondary goal of the ILIAD protocol is to maintain a registry of cases in the ILIAD database so that they may be recontacted in the future. It is expected that this will facilitate additional studies exploring the mechanisms of DILI. Targeted Drugs: The initial drugs to be targeted in the ILIAD protocol are isoniazid (INH), phenytoin, clavulanic acid / amoxicillin (Augmentin and valproic acid. For INH, phenytoin, or clavulanic acid / amoxicillin, severe liver injury is defined as a documented serum total bilirubin > 2.5 mg/dl; for valproic acid, the criteria are compatible symptomatic clinical presentation that is severe enough to prompt hospitalization and evidence of liver dysfunction International normalized ratio (INR) > 1.5 or Alanine transaminase (ALT) > 3 X Upper Limit of Normal (ULN), and/or characteristic liver biopsy). The target drugs were chosen because they cause severe DILI at a high rate compared with other drugs, making our target enrollment for each drug (n = 50-100) attainable. In addition, these drugs are frequently administered to reasonably healthy patients not concurrently receiving other drugs more likely to be hepatotoxic, facilitating causation assessment. Basic Study Design: The five DILIN clinical centers will identify and contact patients at their own and affiliated institutions who may have suffered a liver injury due to one of the targeted drugs. They will also contact gastroenterologists, hepatologists, and other health care professionals most likely to have treated DILI cases. In the latter case, an information packet will be sent by the treating physician to the potential subject, and interested subjects will be requested to contact one of the five clinical sites. In either case, the subject will be given a brief description of the study's purpose and procedures, and when further interest in the study is expressed, s/he will be mailed provided with an information packet including the informed consent document, The Health Insurance Portability and Accountability Act (HIPAA) authorization and release of medical record forms. Once these documents have been received reviewed by the subject, study staff will contact the potential subject by telephone a second time. This follow-up contact will either occur by telephone or in person at the subject's convenience. Informed consent will be obtained, and if this occurs over the telephone, it will be witnessed by a third party on the line. Then, requisite information will be collected using a telephone or personal interview format. Prior to ending this phone call the end of the second contact, the subject will be asked to sign the consent, HIPAA authorization, and release of medical information forms and return provide them to the DILIN clinical site. Arrangements for blood drawing will be made. The blood sample will be shipped to the Rutgers University Cell and DNA Repository (RUCDR) where DNA will be extracted and lymphocytes will be immortalized. DNA, plasma and immortalized lymphocytes will be frozen and stored for future studies. Once the signed documents have been received, medical records and charts will also be retrieved from the appropriate health care provider(s). Detailed clinical information concerning the DILI event will be abstracted from the charts and entered onto case report forms. This information will then be reviewed by the DILIN Causality Committee, and it will make the final determination on whether the patient was a true DILI case.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 背景和理由：药物性肝损伤 (DILI) 是药物监管行动的最常见原因，包括未能获得上市批准、从市场上撤出以及限制处方适应症。 药源性肝损伤也是许多患者群体发病和死亡的重要原因。 为了刺激和促进对 DILI 的研究，国家糖尿病、消化和肾脏疾病研究所 (NIDDK) 最近建立了药物性肝损伤网络 (DILIN)。 该网络最初开展的项目之一是回顾性建立全国范围内因药物引起的严重特异质肝损伤（ILIAD）患者的登记，并收集、永生化和储存这些患者的血清、脱氧核糖核酸（DNA）和淋巴细胞（以下简称“ILIAD方案”）。 该 ILIAD 协议将作为后续对严重特殊 DILI 易感性基础的机制调查的资源。 具体目的和目标： ILIAD 方案的主要目标是创建： (a) 一个临床数据库，其中包含曾经历过由四种特定药物引起的严重 DILI 的个体，以及有关 DILI 发作的相关临床数据； (b) 创建从这些个体获得的生物样本库。 来自对照对象的相应信息也将被收集。 这些生物样本将是DNA、血浆和永生化淋巴细胞。 永生化淋巴细胞将为研究提供无限量的基因组 DNA，并为表型研究提供活体免疫细胞。 ILIAD 协议的第二个目标是在 ILIAD 数据库中维护病例登记，以便将来可以重新联系它们。 预计这将有助于进一步研究 DILI 的机制。 靶向药物：ILIAD方案中的初始靶向药物是异烟肼（INH）、苯妥英、克拉维酸/阿莫西林（Augmentin和丙戊酸）。对于INH、苯妥英或克拉维酸/阿莫西林，严重肝损伤定义为记录的血清总胆红素> 2.5 mg/dl；对于丙戊酸，严重肝损伤定义为记录的血清总胆红素> 2.5 mg/dl。 标准是符合症状的临床表现，严重到足以促使住院，并且有肝功能障碍的证据，国际标准化比值 (INR) > 1.5 或丙氨酸转氨酶 (ALT) > 3 X 正常上限 (ULN)，和/或特征性肝活检）。选择目标药物是因为与其他药物相比，它们引起严重 DILI 的几率较高，从而可以实现每种药物的入组目标 (n = 50-100)。 此外，这些药物经常用于相当健康的患者，而不是同时接受其他更有可能具有肝毒性的药物，从而有利于因果关系评估。 基本研究设计：五个 DILIN 临床中心将识别并联系其自己和附属机构中可能因其中一种靶向药物而遭受肝损伤的患者。 他们还将联系胃肠病学家、肝病学家和其他最有可能治疗过 DILI 病例的医疗保健专业人员。 在后一种情况下，治疗医生将向潜在受试者发送信息包，并且将要求感兴趣的受试者联系五个临床站点之一。 无论哪种情况，都会向受试者简要描述研究的目的和程序，当受试者表达出对研究的进一步兴趣时，他/她将收到一个信息包，其中包括知情同意文件、健康保险流通和责任法案 (HIPAA) 授权以及医疗记录表格的发布。 一旦受试者审查完这些文件，研究人员将再次通过电话联系潜在受试者。 这种后续联系将通过电话或在对象方便时亲自进行。 将获得知情同意，如果通过电话进行，则将由在线第三方见证。 然后，将通过电话或个人访谈的形式收集必要的信息。 在结束本次电话通话或第二次联系结束之前，将要求受试者签署同意书、HIPAA 授权、发布医疗信息表并将其返回给 DILIN 临床站点。 将安排抽血。 血液样本将被运送到罗格斯大学细胞和 DNA 存储库 (RUCDR)，在那里提取 DNA 并使淋巴细胞永生化。 DNA、血浆和永生化淋巴细胞将被冷冻并储存以供未来研究。 收到签署的文件后，还将从适当的医疗保健提供者处检索医疗记录和图表。 有关 DILI 事件的详细临床信息将从图表中提取并输入到病例报告表中。 然后，DILIN 因果关系委员会将审查这些信息，并最终确定该患者是否是真正的 DILI 病例。