ILIAD

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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、从市场上撤下以及处方适应症的限制。DILI也是许多患者发病和死亡的一个重要原因。为了刺激和促进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）。该网络开展的最初项目之一是回顾性地建立一个全国性的药物相关严重特异性肝损伤患者登记册（ILIAD），并收集、永久保存这些患者的血清、DNA和淋巴细胞（以下简称“ILIAD方案”）。该ILIAD方案将作为对严重特异性DILI易感性基础的后续机制调查的资源。具体目的和目标：ILIAD方案的主要目标是建立：(a)一个临床数据库，包括经历过由四种特定药物引起的严重DILI的个人，以及与DILI发作有关的临床数据；(b)建立从这些个体获得的生物标本库。对照受试者的相应信息也将被收集。这些生物标本包括DNA、血浆和永生淋巴细胞。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的免疫细胞。ILIAD协议的第二个目标是在ILIAD数据库中维护病例注册表，以便将来可以重新联系他们。预计这将有助于进一步研究DILI的机制。靶向药物：在ILIAD方案中，最初的靶向药物是异烟肼、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，重度肝损伤定义为血清总胆红素≥2.5 mg/dl；对于丙戊酸，标准是符合症状性临床表现，严重到足以促使住院治疗和肝功能障碍的证据（INR 1.5或ALT 3 × 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，这些药物导致严重DILI的发生率较高，这使得我们可以实现每种药物的目标入组（n = 50-100）。此外，这些药物经常用于健康的患者，而不是同时接受其他更可能具有肝毒性的药物，从而促进了因果关系的评估。基础研究设计：五个DILIN临床中心将在自己和附属机构中识别并联系可能因其中一种靶向药物而遭受肝损伤的患者。他们还将联系最有可能治疗过DILI病例的胃肠病学家、肝病学家和其他卫生保健专业人员。在后一种情况下，治疗医师将向潜在受试者发送信息包，并要求感兴趣的受试者与五个临床站点之一联系。在任何一种情况下，受试者都将被告知研究的目的和程序的简要说明，当受试者表示对研究有进一步的兴趣时，我们将邮寄给他/她一个信息包，其中包括知情同意文件、HIPAA授权和医疗记录表格的发布。一旦受试者收到这些文件，研究人员将通过电话与潜在受试者进行第二次联系。这种后续联系将在受试者方便时通过电话或亲自进行。知情同意将获得，如果这发生在电话上，它将由在线的第三方见证。然后，必要的信息将通过电话或个人面试的形式收集。在电话结束前，即第二次联系结束时，受试者将被要求签署同意书、HIPAA授权和医疗信息表，并将其返还给DILIN临床站点。抽血的安排将会安排。血液样本将被运送到罗格斯大学细胞和DNA储存库（RUCDR），在那里提取DNA，并使淋巴细胞永生。DNA、血浆和永生化淋巴细胞将被冷冻保存，以备将来的研究。一旦收到签署的文件，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病例报告表格。然后，DILIN因果关系委员会将审查这些信息，并最终确定患者是否为真正的DILI病例。

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, 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, 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 (INR > 1.5 or ALT > 3 X 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, 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.