ILIAD

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景和理论：药物性肝损伤(DILI)是药品监管行为最常见的单一原因，包括未能获得上市批准、从市场下架和限制开药适应症。在许多患者群体中，DILI也是发病率和死亡率的重要原因。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)最近建立了药物诱导肝损伤网络(DILIN)。该网络将开展的初步项目之一是在全国范围内建立与药物相关的严重特异性肝损伤患者登记(Iliad)，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(以下称为“Iliad方案”)。这份《伊利亚特议定书》将作为随后对严重特质的帝力易感性基础进行机械性调查的资源。 具体目的和目标：《伊利亚特议定书》的主要目标是：(A)建立一个临床数据库，其中包括经历过由四种特定药物引起的严重DILI的个人，以及有关DILI发作的相关临床数据；和(B)建立从这些人那里获得的生物标本库。来自对照对象的相应信息也将被收集。这些生物标本将是DNA、血浆和永生化的淋巴细胞。永生化淋巴细胞将为研究提供无限数量的基因组DNA，并为表型研究提供活的免疫细胞。《伊利亚特议定书》的第二个目标是在伊利亚特数据库中维持案件登记处，以便今后可以重新联系这些案件。预计这将有助于对帝力机制进行更多的研究。 靶向药物：伊利亚特方案中最初的靶向药物是异烟肼(INH)、苯妥英、克拉维酸/阿莫西林(Augentin和丙戊酸)。对于异烟肼、苯妥英或克拉维酸/阿莫西林，严重肝损伤定义为有文件记载的血清总胆红素2.5 mg/dl；对于丙戊酸，标准是符合症状的临床表现，严重到足以促使住院和肝功能障碍的证据(国际标准化比率(INR)&gt；1.5或丙氨酸转氨酶(ALT)&gt；3X正常上限(ULN)，和/或特征性肝活检)。之所以选择目标药物，是因为与其他药物相比，它们导致严重DILI的比率很高，使我们每种药物(n=50-100)的目标登记都可以实现。此外，这些药物经常用于健康状况良好的患者，而不是同时接受其他更有可能对肝脏有毒性的药物，这有助于因果关系评估。 基础研究设计：五个DILIN临床中心将识别并联系各自机构及其附属机构中可能因目标药物之一而遭受肝脏损伤的患者。他们还将联系胃肠病专家、肝病专家和其他最有可能治疗过DILI病例的卫生保健专业人员。在后一种情况下，治疗医生将向潜在受试者发送信息包，并要求感兴趣的受试者联系五个临床站点中的一个。在任何一种情况下，受试者都将被简要描述研究的目的和程序，当对研究表示进一步的兴趣时，S将被邮寄一份信息包，其中包括知情同意文件、《健康保险携带和责任法案》授权和医疗记录表格的发布。一旦受试者收到这些文件，研究人员将通过第二次电话联系潜在受试者。后续联系将通过电话进行，或在受试者方便时亲自进行。将获得知情同意，如果这发生在电话上，将由第三方在线见证。然后，将通过电话或个人面谈的形式收集必要的信息。在此电话通话结束之前，第二次联系结束时，受试者将被要求签署同意书、HIPAA授权、医疗信息表的发布并将其提供给DILIN临床站点。抽血的安排将会安排。血液样本将被运往罗格斯大学细胞和DNA存储库(RUCDR)，在那里将提取DNA，并使淋巴细胞永生。DNA、血浆和永生化淋巴细胞将被冷冻和储存，以供未来研究。一旦收到签署的文件，还将从适当的医疗保健提供者(S)那里检索医疗记录和图表。关于帝力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格中。这些信息随后将由DILIN因果关系委员会审查，并将对患者是否为真正的DILI病例做出最终确定。

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.