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: 10454802
• 负责人: Elliot Israel
• 金额: $ 43.43万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454802
• 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; 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.

项目总结