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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景和依据：药物性肝损伤（DILI）是药物相关监管措施的最常见原因，包括未能获得上市批准、从市场上撤市和限制处方适应症。 DILI也是许多患者人群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）。 该网络将开展的初步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质肝损伤患者登记处（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（以下简称“ILIAD方案”）。 该ILIAD方案将作为后续对重度特异质DILI易感性基础的机制研究的资源。 具体目的和目标：ILIAD方案的主要目标是创建：（a）由经历过由四种特定药物引起的重度DILI的个体以及关于DILI发作的相关临床数据组成的临床数据库;以及（B）创建从这些个体获得的生物标本库。 还将收集对照受试者的相应信息。 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，以及用于表型研究的活免疫细胞。 ILIAD方案的第二个目标是在ILIAD数据库中维护病例登记，以便将来可以重新联系。 预计这将有助于探索DILI机制的其他研究。 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，严重肝损伤定义为血清总胆红素> 2.5 mg/dl;对于丙戊酸，标准是相容的症状性临床表现，其严重程度足以促使住院治疗和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倍正常上限（ULN），和/或特征性肝脏活检）。选择目标药物是因为与其他药物相比，它们导致严重DILI的发生率很高，这使得我们可以实现每种药物的目标入组人数（n = 50-100）。 此外，这些药物经常用于未同时接受其他更可能具有肝毒性的药物的合理健康患者，便于因果关系评估。 基础研究设计：五个DILIN临床中心将在自己的机构和附属机构中识别和联系可能因靶向药物之一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，主治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家临床研究中心之一。 在任何一种情况下，将向受试者简要描述研究目的和程序，并且当表达对研究的进一步兴趣时，将向她/他邮寄信息包，包括知情同意文件、健康保险携带和责任法案（HIPAA）授权和病历表发布。 一旦受试者审查了这些文件，研究工作人员将再次通过电话联系潜在受试者。 该随访联系将在受试者方便时通过电话或亲自进行。 将获得知情同意，如果通过电话进行，将由第三方在线见证。 然后，将通过电话或个人访谈的形式收集必要的信息。 在第二次联系结束之前，将要求受试者签署知情同意书、HIPAA授权书和医疗信息发布表，并将其返回DILIN临床研究中心。 将安排抽血。 血液样本将被运送到罗格斯大学细胞和DNA储存库（RUCDR），在那里将提取DNA并将淋巴细胞永生化。 DNA、血浆和永生化淋巴细胞将被冷冻并储存用于未来的研究。 一旦收到已签署的文件，还将从适当的医疗保健提供者处检索病历和图表。 将从图表中提取关于DILI事件的详细临床信息，并输入病例报告表。 DILIN因果关系委员会将对这些信息进行审查，并最终确定患者是否为真正的DILI病例。