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: 10402818
• 负责人: Elizabeth Phillips
• 金额: $ 331.68万
• 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/10402818
• 关键词: Acute; Address; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; African; African American population; 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; Hispanic Americans; 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; antagonist; 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; risk stratification; screening; screening program; secondary outcome; sex; southeast Asian; standard of care; targeted treatment; transcriptome; transcriptomics; treatment arm; treatment effect; treatment response; 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.

项目概要 史蒂文斯-约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 非常严重，危及生命 免疫介导的药物不良反应代表同一疾病的不同严重程度。1 目前尚无 SJS/TEN 护理治疗的循证标准。预防工作已 在 HLA I 类等位基因 HLA-B*15:02 之间的强烈关联的推动下，这导致了 许多东南亚国家开展了具有成本效益的治疗前基因筛查计划。2,3 然而， 该 HLA 等位基因在欧洲裔美国人、西班牙裔美国人中的患病率较低（<1%）和阴性预测值 美国人和非裔美国人群体，以及目前缺乏明确的 HLA 与药物的关联 在美国，与 SJS/TEN 相关的常用方法留下了许多证据空白， 实施障碍。4 这项研究的科学前提是最有效的治疗方法是 影响 SJS/TEN 介导的细胞免疫反应、相关生物标志物和临床结果。我们 汇集了北美表皮坏死松解综合征治疗 (NATIENS) 研究， 美国 22 个地点开展首次多中心双盲双模拟 环孢素或依那西普或支持治疗的随机对照评估。受控的 设计将提供在每个治疗组中收集和分析多个样本的机会，无论是 急性期和恢复期，旨在发现新的预防策略，及早 诊断和针对性治疗。我们将使用集成的多组学、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 药物引起的 SJS/TEN。在具体目标 1 中，我们将为 SJS/TEN 建立临床上最有效的疗法 通过NATIENS多中心、双盲双模拟随机对照试验，计划 在 5 年入组期间对 267 名患者进行了统计，以确定依那西普和/或环孢素是否具有 对于测量的完全上皮化的主要结果，优于支持性护理。特定目标 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 识别预测 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 研究急性 SJS/TEN 皮肤、疱液和外周血细胞的免疫表型 单细胞RNA和蛋白质表达。使用水泡中占主导地位的 T 细胞受体 (TCR) 我们将使用高通量体外筛选方法来识别 CD8+ 识别的特定表位 SJS/TEN 组织损伤部位的 T 细胞。5 我们的研究将是第一个双盲研究 SJS/TEN 的管理和机制的随机对照设计。这将带来新的方式 预防、诊断和治疗 SJS/TEN，并将为严重的研究制定路线图和证据基础 免疫介导的药物不良反应和其他免疫介导的疾病。