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: 10612063
• 负责人: Elizabeth Phillips
• 金额: $ 350.74万
• 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/10612063
• 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; Epithelium; 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 Antigen Receptor Specificity; T-Cell Receptor; Testing; Therapeutic; Time; Tissues; Toxic Epidermal Necrolysis; Treatment outcome; Tumor Necrosis Factor Receptor; United States; Urine; Variant; adverse drug reaction; antagonist; 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; outcome prediction; peripheral blood; phase 3 study; predictive marker; prevent; primary outcome; protein expression; randomized controlled design; repository; risk prediction; 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.

项目总结

项目成果

Delabeling Delayed Drug Hypersensitivity: How Far Can You Safely Go?

• DOI: 10.1016/j.jaip.2020.07.005
• 发表时间: 2020-10
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Lehloenya RJ;Peter JG;Copascu A;Trubiano JA;Phillips EJ
• 通讯作者: Phillips EJ

Reporting of drug reaction with eosinophilia and systemic symptoms from 2002 to 2019 in the US Food and Drug Administration Adverse Event Reporting System.

• DOI: 10.1016/j.jaip.2021.05.008
• 发表时间: 2021-08
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Bluestein SB;Yu R;Stone C Jr;Phillips EJ
• 通讯作者: Phillips EJ

Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors.

• DOI: 10.1038/s42003-022-03058-9
• 发表时间: 2022-02-16
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Sooda A;Rwandamuriye F;Wanjalla CN;Jing L;Koelle DM;Peters B;Leary S;Chopra A;Calderwood MA;Mallal SA;Pavlos R;Watson M;Phillips EJ;Redwood AJ
• 通讯作者: Redwood AJ

Anti-PEG IgE in anaphylaxis associated with polyethylene glycol.

与聚乙二醇相关的过敏反应中的抗PEG IgE。

• DOI: 10.1016/j.jaip.2020.11.011
• 发表时间: 2021-04
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Zhou ZH;Stone CA Jr;Jakubovic B;Phillips EJ;Sussman G;Park J;Hoang U;Kirshner SL;Levin R;Kozlowski S
• 通讯作者: Kozlowski S

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach.

• DOI: 10.1016/j.jaip.2020.12.047
• 发表时间: 2021-04
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Banerji A;Wickner PG;Saff R;Stone CA Jr;Robinson LB;Long AA;Wolfson AR;Williams P;Khan DA;Phillips E;Blumenthal KG
• 通讯作者: Blumenthal KG