PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma

PATINA - 中性粒细胞性严重哮喘的精准治疗

• 批准号: 10216322
• 负责人: Elliot Israel
• 金额: $ 48.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216322
• 关键词: Adrenal Cortex Hormones; Adult asthma; Advisory Committees; Aftercare; Algorithms; Arachidonate 5-Lipoxygenase; Area; Asthma; Biochemical; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biology; C-reactive protein; CCL3 gene; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chemotactic Factors; Childhood; Childhood Asthma; Clinical Research; Data; Eicosanoids; Environment; Exhalation; Futility; Future; Genetic Polymorphism; Genomics; IL6 gene; Imatinib; Immunobiology; Industry; Inflammation; Inflammatory; Insulin Resistance; Interleukin 6 Receptor; Interleukin-6; Intervention; Knowledge; Letters; Leukotriene B4; Lipoxygenase Inhibitors; Methodology; Morbidity - disease rate; Mus; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Placebos; Population; Production; Publishing; Recording of previous events; Request for Proposals; Research Design; Risk; Running; Seasons; Serum; Signal Transduction; Single-Blind Study; Specific qualifier value; Sputum; Stem Cell Factor; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Tryptase; Urine; Work; arm; asthmatic; base; biomarker development; biomarker discovery; biomarker validation; candidate marker; cohort; cysteinyl-leukotriene; design; effective therapy; experience; falls; genomic RNA; improved; inhibitor/antagonist; innovation; macrophage; mast cell; neutrophil; phenotypic biomarker; predictive marker; pulmonary function; recruit; responders and non-responders; response; response biomarker; targeted treatment; treatment arm; trial design; urinary

Project Summary Severe asthma accounts for a disproportionate share of the morbidity associated with asthma. Multiple biological therapies are now becoming available that target eosinophilic or Type 2- driven asthma. However, data from SARP indicate that >60% of patients have severe asthma with a neutrophilic phenotype (SANP), as defined by induced sputum differentials. These patients experience excess morbidity, and there are currently no therapies that effectively target neutrophilic inflammation. We recently completed a study wherein we showed that targeting mast cells with imatinib (an inhibitor of stem-cell factor signaling at KIT) was most effective in patients with a neutrophilic phenotype. Further, we found that reductions in serum tryptase could identify patients most likely to respond to this treatment. Additionally, we have shown that in severe asthma, despite aggressive corticosteroid therapy (which normally reduces inflammatory eicosanoids) these patients continue to elaborate pro-inflammatory eicosanoids and low-pro-resolving eicosanoids. This is indicated by our discovery of persistent elevation of LTB4 (which is a potent neutrophil chemoattractant) in exhaled breath condensate. Lastly, IL-6 has been associated with non-Type 2 asthma, insulin resistance, and TH17 skewing of CD4+ cells. IL6 receptor polymorphisms have been associated with asthma risk, and high IL6 has been associated with reduced lung function and increased exacerbations, even in a cohort of severe asthmatics. We posit the following set of primary hypotheses and in each case we list the severe asthma phenotype and its phenotype marker(s) (PM), our primary candidate response marker at 2 months (RM) (in parentheses our secondary RMs), and the targeted intervention (TI). Our hypotheses are that in subjects with : 1) SANP with high serum IL6 (PM), a fall in—C-reactive protein (TH17 cells, insulin resistance ) (RM), will identify those more likely to improve after anti-IL6 therapy (TI); 2) SANP with high exhaled LTB4 (PM), a fall in exhaled LTB4 (urinary cysteinyl leukotrienes) (RM) will identify those more likely to improve with a 5- lipoxygenase inhibitor (5-LOi) (that blocks production of pro-inflammatory eicosanoids); 3) Severe asthma with increased sputum neutrophils (PM), a fall in serum tryptase (sputum supernatant tryptase) (RM) will identify asthmatics more likely to improve after treatment with a KIT inhibitor (TI). Our adaptive study design and treatment approach will allow us to define the threshold values of our RM that identify patients with a higher likelihood of response to targeted therapy. We have a team of seasoned trialists in adult and pediatric asthma, experts in biomarker development, the mechanisms behind these biomarkers, and adaptive trial design and integrative analyses, which will add significant strength to a PRECISE network.

项目摘要 严重的哮喘占与哮喘相关的发病率的不成比例。 现在正在使用多种生物疗法，以靶向嗜酸性粒细胞或2-型 驱动哮喘。但是，来自SARP的数据表明> 60％的患者患有严重的哮喘 由诱导的痰液差异定义的中性粒细胞表型（SANP）。这些 患者经历超过发病率，目前尚无有效靶向的疗法 中性粒细胞炎症。我们最近完成了一项研究，其中我们表明了目标 用伊马替尼的肥大细胞（试剂盒中的干细胞因子信号传导的抑制剂）最有效 患有嗜中性粒细胞型的患者。此外，我们发现血清胰蛋白酶的减少 可以识别最有可能对此治疗反应的患者。此外，我们已经表明 在严重的哮喘中，dospite攻击性皮质类固醇治疗（通常会降低 炎症类花生酸）这些患者继续详细介绍促炎的类花生酸酯 和低培养的类花生酸酯。这是我们发现的 LTB4（这是一种潜在的中性粒细胞趋化剂）中的呼吸凝结物。最后，IL-6 与非型2哮喘，胰岛素抵抗和CD4+的Th17偏斜有关 细胞。 IL6受体多态性与哮喘风险有关，高6个 与肺功能降低和加重有关，即使在一组 严重的哮喘患者。我们提倡以下一组主要假设，在每种情况下，我们列出 严重的哮喘表型及其表型标记（S）（PM），我们的主要候选人 2个月（RM）的响应标记（在我们的次级RMS中），目标是 干预（TI）。我们的假设是：1）具有高血清IL6（PM）的SANP， 落入-c反应性蛋白（Th17细胞，胰岛素抵抗）（RM），将识别出更可能的 在抗IL6治疗后改善（TI）； 2）SANP耗尽LTB4（PM），疲惫不堪 LTB4（尿胱烷酰白细胞）（RM）将确定那些更有可能通过5-- 脂氧合酶抑制剂（5-LOI）（阻止促炎性类固醇的产生）； 3） 严重的哮喘患有痰中性粒细胞增加（PM），血清胰蛋白酶降低（痰液） 上清液胰蛋白酶）（RM）将确定哮喘患者在治疗后更有可能改善 试剂盒抑制剂（TI）。我们的自适应研究设计和治疗方法将使我们能够定义 我们的RM的阈值识别对目标的反应可能性较高的患者 治疗。我们有一个成人和儿科哮喘的经验丰富的试验者，专家 生物标志物开发，这些生物标志物背后的机制以及自适应试验设计 并集成的分析，这将为精确的网络增加大量的强度。