NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

NATIENS：一项 III 期随机双盲研究，以确定史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的机制和最佳治疗

• 批准号: 10217036
• 负责人: Elizabeth Phillips
• 金额: $ 353.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217036
• 关键词: Acute; Address; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; African; African American; Age; Alleles; American; Antigens; Automobile Driving; Biological; Biological Assay; Biological Markers; Blinded; Blood; Body Surface Area; Bulla; CD8-Positive T-Lymphocytes; Carbamazepine; Cell Surface Proteins; Cells; Clinical; Country; Cryopreservation; Cyclosporine; DNA; Diagnosis; Disease; Disease Progression; Double-Blind Method; Drug Design; Drug Exposure; Drug Kinetics; Drug Tolerance; Early Diagnosis; Emergency Situation; Enrollment; Epithelial; Epitopes; Etanercept; Ethnic Origin; European; Evidence based treatment; Exposure to; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Screening; Genetic Transcription; Geography; HLA Antigens; Half-Life; Hispanic Americans; Hispanics; Histocompatibility Antigens Class I; Immune; Immune response; Immunologics; In Vitro; Intensive Care; Intervention; Intravenous Immunoglobulins; Knowledge; Left; Length of Stay; Level of Evidence; Life; Liquid substance; Low Prevalence; Measures; Mediating; Molecular Profiling; Morbidity - disease rate; Multicenter Studies; Observational Study; Outcome; Patient-Focused Outcomes; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Population; Population Control; Predictive Value; Prevention; Prevention strategy; Preventive; Prognosis; RNA; Race; Randomized; Randomized Controlled Trials; Reporter; Research; Resolution; Risk; Risk Factors; Role; Sampling; Severities; Severity of illness; Site; Skin; Southeastern Asia; Specificity; Stevens-Johnson Syndrome; Subgroup; Supportive care; Syndrome; T-Cell Receptor; Testing; Therapeutic; Time; Tissues; Toxic Epidermal Necrolysis; Treatment outcome; Tumor Necrosis Factor Receptor; United States; Urine; Variant; adverse drug reaction; base; biobank; clinical care; cost effective; cytokine; design; effective therapy; efficacious treatment; evidence base; follow-up; genome-wide; high risk; human leukocyte antigen testing; immunomodulatory therapies; immunopathology; implementation cost; improved; infection rate; mortality; multiple omics; novel; optimal treatments; peripheral blood; phase 3 study; predictive marker; prevent; primary outcome; protein expression; randomized controlled design; repository; response; risk stratification; screening; screening program; secondary outcome; sex; southeast Asian; standard of care; targeted treatment; transcriptome; transcriptomics; treatment arm; treatment effect; treatment strategy

PROJECT SUMMARY Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are severe, life-threatening immunologically mediated adverse drug reactions representing the same disease across a spectrum of severity.1 There is currently no evidence-based standard of care treatment for SJS/TEN. Preventive efforts have been fueled by strong associations between the HLA Class I allele HLA-B*15:02 which has led to implementation of cost-effective pre-treatment genetic screening programs in many Southeast Asian countries.2,3 However, the lower prevalence (<1%) and negative predictive value of this HLA allele in European American, Hispanic American, and African American populations, and the lack of currently defined HLA associations with drugs commonly used and associated with SJS/TEN in the United States has left many evidence gaps and implementation hurdles.4 The scientific premise of this study is that the most efficacious treatment will impact cellular immune responses mediating, related biomarkers and clinical outcomes of SJS/TEN. We have assembled the North American Therapeutics in Epidermal Necrolysis Syndrome (NATIENS) study, a group of 22 sites across the United States to conduct the first multicenter double-blind double dummy randomized controlled assessment of cyclosporine or etanercept or supportive care. The controlled design will afford the opportunity to collect and assay multiple samples in each treatment arm, in both the acute and convalescent phase, with the aim to discover new strategies for prevention, early diagnosis and targeted treatment. We will use integrated multi-omic, single-cell and high-throughput in-vitro screening approaches to determine the genetic basis, immunopathology and antigen specificity of drug-induced SJS/TEN. In Specific Aim 1 we will establish the most clinically effective therapy for SJS/TEN through the NATIENS multi-centered, double-blind double-dummy randomized controlled trial with a planned accrual of 267 patients over 5 enrollment years to determine whether etanercept and/or cyclosporine have benefit over supportive care for the measured primary outcome of complete re-epithelialization. In Specific Aim 2 we will use genome-wide sequencing, high-resolution HLA sequencing, transcriptomic, and cytokine profiling to identify genetic and biological markers that predict risk and outcome for SJS/TEN. In Specific Aim 3 We will study the immune phenotype of cells in the skin, blister fluid and peripheral blood in acute SJS/TEN based on single-cell RNA and protein expression. Using the dominantly represented T-cell receptor (TCR) in the blister fluid we will use a high throughput in-vitro screening approach to identify specific epitopes recognized by CD8+ T cells at the site of SJS/TEN tissue damage.5 Our study will be the first to examine in a double-blind randomized controlled design both management and mechanisms of SJS/TEN. This will lead to new ways to prevent, diagnosis and treat SJS/TEN, and will create a roadmap and evidence-base for studies of serious immunologically-mediated adverse drug reactions and other immunologically-mediated diseases.

项目摘要 史蒂文斯 - 约翰逊综合症（SJS）和有毒表皮坏死溶解（十），严重，威胁生命 免疫学介导的不良药物反应代表了一系列严重程度的相同疾病。1 目前尚无针对SJS/10的基于证据的护理水平治疗。预防努力是 由HLA I级等位基因HLA-B*15：02之间的牢固关联所推动的，这导致了实施 在许多东南亚国家中，具有成本效益的遗传筛查计划。2,3但是， 在欧美，西班牙裔中，该HLA等位基因的较低患病率（<1％）和负预测价值 美国和非裔美国人的人口，以及目前缺乏与毒品的HLA关联 在美国，常用并与SJS/10相关联，留下了许多证据差距， 实施障碍。4这项研究的科学前提是，最有效的治疗方法将 影响细胞免疫反应介导，相关的生物标志物和SJS/10的临床结果。我们 在表皮坏死综合征（Natiens）研究中组装了北美治疗剂， 整个美国的22个地点组成的小组进行了第一个多中心双盲双假人 环孢霉素或依那酚或支持护理的随机对照评估。受控 设计将有机会在每个治疗臂中收集和分析多个样本 急性和康复阶段，目的是发现预防的新策略，早期 诊断和靶向治疗。我们将使用集成的多机，单细胞和高通量 维特罗筛查方法以确定遗传基础，免疫病理学和抗原特异性 药物诱导的SJS/10。在特定目标1中，我们将建立针对SJS/TEN的最有效的疗法 通过Natiens多中心，双盲双人杀人随机对照试验，并计划 在5个入学年内的267名患者的应计，以确定依那西普和/或环孢菌素是否具有 对完全重新上皮化的主要主要结果的支持性护理的好处。在特定目标中 2我们将使用全基因组测序，高分辨率HLA测序，转录组和细胞因子分析 确定预测SJS/10的风险和结果的遗传和生物学标记。在特定目标3中，我们将 根据急性SJ/TEN中的皮肤中细胞的免疫表型，水泡液和外周血 单细胞RNA和蛋白质表达。使用在水泡中主要代表的T细胞受体（TCR） 流体我们将使用高吞吐量的体外筛查方法来识别CD8+识别的特定表位 SJS/十组织损害部位的T细胞。5我们的研究将是第一个以双盲检查的研究 SJS/10的随机控制设计和机制。这将导致新的方式 为了预防，诊断和治疗SJS/10，并将创建一个路线图和证据基础，以研究严重 免疫介导的不良药物反应和其他免疫学介导的疾病。