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.

项目总结 史蒂文斯-约翰逊综合征(SJS)和中毒性表皮坏死松解症(TEN)是严重的、危及生命的 免疫介导的药物不良反应代表同一种疾病的不同严重程度1 目前对SJS/TEN没有循证护理治疗标准。预防工作一直在进行 由人类白细胞抗原I类等位基因人类白细胞抗原-B*15：02之间的强烈关联推动，这导致了 许多东南亚国家的治疗前基因筛查计划具有成本效益。2，3然而， 该等位基因在欧洲裔美国人和西班牙裔人群中的低患病率(1%)和阴性预测价值 美国人、非裔美国人和非裔美国人群体，以及目前确定的与药物有关的人类白细胞抗原 在美国广泛使用和与SJS/TEN有关的证据留下了许多空白和 实施障碍。4这项研究的科学前提是最有效的治疗将 影响细胞免疫反应、相关生物标志物和SJS/TEN的临床转归。我们 已经汇集了北美治疗表皮坏死松解综合征(NATIENS)的研究， 由22个地点组成的团体在全美范围内进行了首个多中心双盲双假人 环孢素、依那西普或支持性治疗的随机对照评估。受控者 设计将提供在每个治疗臂中收集和分析两种方法中的多个样本的机会 急性期和恢复期，旨在及早发现新的预防战略 诊断和靶向治疗。我们将使用集成的多组、单细胞和高通量 确定遗传基础、免疫病理学和抗原特异性的体外筛选方法 药物诱导的SJS/TEN。在特定的目标1中，我们将建立对SJS/TEN最有效的临床治疗方法 通过NATIENS多中心、双盲、双模拟、随机对照试验 确定依那西普和/或环孢素是否有疗效的267名患者在5个登记年度内的收益 与支持性护理相比，完全再上皮化的可测量的主要结果是有益的。以特定的目标 2我们将使用全基因组测序、高分辨率的人类白细胞抗原测序、转录和细胞因子分析 确定预测SJS/TEN风险和结果的遗传和生物标记。在具体目标3中，我们将 急性SJS/TEN患者皮肤、疱液及外周血细胞免疫表型的研究 单细胞RNA和蛋白质的表达。利用水泡中主要代表的T细胞受体(TCR) 我们将使用高通量的体外筛选方法来鉴定CD8+识别的特定表位 在SJS/TEN组织损伤部位的T细胞。5我们的研究将是第一次双盲检查 SJS/TEN的管理和作用机制的随机对照设计。这将导致新的方式 预防、诊断和治疗SJS/TEN，并将为研究严重的 免疫介导的药物不良反应和其他免疫介导的疾病。