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
基本信息
- 批准号:10217036
- 负责人:
- 金额:$ 353.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAdrenal Cortex HormonesAdultAdverse effectsAffectAfricanAfrican AmericanAgeAllelesAmericanAntigensAutomobile DrivingBiologicalBiological AssayBiological MarkersBlindedBloodBody Surface AreaBullaCD8-Positive T-LymphocytesCarbamazepineCell Surface ProteinsCellsClinicalCountryCryopreservationCyclosporineDNADiagnosisDiseaseDisease ProgressionDouble-Blind MethodDrug DesignDrug ExposureDrug KineticsDrug ToleranceEarly DiagnosisEmergency SituationEnrollmentEpithelialEpitopesEtanerceptEthnic OriginEuropeanEvidence based treatmentExposure toFutureGene ExpressionGenesGeneticGenetic MarkersGenetic ScreeningGenetic TranscriptionGeographyHLA AntigensHalf-LifeHispanic AmericansHispanicsHistocompatibility Antigens Class IImmuneImmune responseImmunologicsIn VitroIntensive CareInterventionIntravenous ImmunoglobulinsKnowledgeLeftLength of StayLevel of EvidenceLifeLiquid substanceLow PrevalenceMeasuresMediatingMolecular ProfilingMorbidity - disease rateMulticenter StudiesObservational StudyOutcomePatient-Focused OutcomesPatientsPeptidesPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhasePhenotypePlasmaPopulationPopulation ControlPredictive ValuePreventionPrevention strategyPreventivePrognosisRNARaceRandomizedRandomized Controlled TrialsReporterResearchResolutionRiskRisk FactorsRoleSamplingSeveritiesSeverity of illnessSiteSkinSoutheastern AsiaSpecificityStevens-Johnson SyndromeSubgroupSupportive careSyndromeT-Cell ReceptorTestingTherapeuticTimeTissuesToxic Epidermal NecrolysisTreatment outcomeTumor Necrosis Factor ReceptorUnited StatesUrineVariantadverse drug reactionbasebiobankclinical carecost effectivecytokinedesigneffective therapyefficacious treatmentevidence basefollow-upgenome-widehigh riskhuman leukocyte antigen testingimmunomodulatory therapiesimmunopathologyimplementation costimprovedinfection ratemortalitymultiple omicsnoveloptimal treatmentsperipheral bloodphase 3 studypredictive markerpreventprimary outcomeprotein expressionrandomized controlled designrepositoryresponserisk stratificationscreeningscreening programsecondary outcomesexsoutheast Asianstandard of caretargeted treatmenttranscriptometranscriptomicstreatment armtreatment effecttreatment strategy
项目摘要
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
Stevens-Johnson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疾病的严重程度范围。1
目前尚无针对SJS/TEN的循证标准治疗。预防工作已
由HLA I类等位基因HLA-B*15:02之间的强关联推动,这导致了
在许多东南亚国家,具有成本效益的治疗前遗传筛查计划。2,3然而,
该HLA等位基因在欧洲裔美国人、西班牙裔美国人和美国人中的患病率较低(<1%),
美国人和非洲裔美国人,以及缺乏目前定义的HLA与药物的关联
在美国,通常使用并与SJS/TEN相关的药物留下了许多证据空白,
实施障碍。4这项研究的科学前提是,最有效的治疗将
影响SJS/TEN介导的细胞免疫应答、相关生物标志物和临床结局。我们
已经组装了北美治疗表皮坏死松解综合征(NATIENS)研究,
美国22个研究中心组成的一组,进行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
设计将提供在每个治疗组中采集和测定多个样本的机会,
急性期和恢复期,目的是发现新的预防战略,
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
药物诱导的SJS/TEN。在具体目标1中,我们将为SJS/TEN建立临床上最有效的治疗方法
通过NATIENS多中心、双盲、双模拟随机对照试验,
在5个入组年内招募267名患者,以确定依那西普和/或环孢霉素是否
对于测量的完全上皮再形成的主要结局,其获益超过支持性治疗。具体目标
我们将使用全基因组测序、高分辨率HLA测序、转录组学和细胞因子分析
确定预测SJS/TEN风险和结局的遗传和生物标志物。在第三阶段,我们将
研究急性SJS/TEN中皮肤、水疱液和外周血细胞的免疫表型,
单细胞RNA和蛋白质表达。使用泡罩中占优势的T细胞受体(TCR)
我们将使用高通量体外筛选方法来鉴定CD 8+识别的特异性表位。
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。这将导致新的方法
预防,诊断和治疗SJS/TEN,并将为严重的研究创建路线图和证据基础。
免疫介导的药物不良反应和其他免疫介导的疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Elizabeth Phillips其他文献
Elizabeth Phillips的其他文献
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{{ truncateString('Elizabeth Phillips', 18)}}的其他基金
Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) 2023
史蒂文斯约翰逊综合症/中毒性表皮坏死松解症 (SJS/TEN) 2023
- 批准号:
10682795 - 财政年份:2023
- 资助金额:
$ 353.5万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 353.5万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 353.5万 - 项目类别:
Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors
幸存者中药物引起的史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症相关的遗传风险和长期结果
- 批准号:
10214660 - 财政年份:2019
- 资助金额:
$ 353.5万 - 项目类别:
Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors
幸存者中药物引起的史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症相关的遗传风险和长期结果
- 批准号:
10441271 - 财政年份:2019
- 资助金额:
$ 353.5万 - 项目类别:
Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors
幸存者中药物引起的史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症相关的遗传风险和长期结果
- 批准号:
10018069 - 财政年份:2019
- 资助金额:
$ 353.5万 - 项目类别:
Single Cell definition of pathogenic T cells in Drug-induced Stevens-Johnson-Syndrome/Toxic epidermal necrolysis
药物诱导史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症中致病性 T 细胞的单细胞定义
- 批准号:
9574331 - 财政年份:2018
- 资助金额:
$ 353.5万 - 项目类别:
Stevens-Johnson Syndrome/Toxic Epidural Necrolysis 2017: Building Multidisciplinary Networks to Drive Science and Translation
史蒂文斯-约翰逊综合症/中毒性硬膜外坏死松解术 2017:建立多学科网络以推动科学和翻译
- 批准号:
9261224 - 财政年份:2017
- 资助金额:
$ 353.5万 - 项目类别:
Understanding and preventing HLA-associated drug reactions
了解和预防 HLA 相关药物反应
- 批准号:
8934766 - 财政年份:
- 资助金额:
$ 353.5万 - 项目类别:
Understanding and preventing HLA-associated drug reactions
了解和预防 HLA 相关药物反应
- 批准号:
9100798 - 财政年份:
- 资助金额:
$ 353.5万 - 项目类别:
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