IMPROVE 2: Inhaled Mometasone to Promote Reduction in Vaso-occlusive Events

改进 2：吸入莫米松促进减少血管闭塞事件

基本信息

批准号：
10457893
负责人：
Jeffrey Avins Glassberg
金额：
$ 76.89万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457893
关键词：
Address Adrenal Cortex Hormones Adverse event Affect Aging Asthma Biological Biological Assay Biological Markers Blood Cells Cessation of life Clinical Clinical Trials Cost Savings Coughing Cytometry Data Diagnosis Disease Disease Outcome Enrollment Erythrocytes Evaluation Event Exhibits Expenditure FCGR3B gene Flow Cytometry Funding Future Goals Health Care Costs Hematology Hemoglobin Hemolysis Immunology Immunophenotyping Individual Inflammation Inflammatory Inhalation Investigation Knowledge Lead Lung Measures Mediator of activation protein Monitor Morbidity - disease rate Mus Organ Pain Patient Outcomes Assessments Patients Pattern Phenotype Placebos Play Preparation Procedures Protocols documentation Pulmonary Inflammation Pulmonology Rest Reticulocytes Risk Factors Role Safety Series Serious Adverse Event Sickle Cell Anemia Sputum Steroids Symptoms System TNF gene Testing Time Translating Translational Research Validation Wheezing acute care adjudicate adverse event monitoring aged blind cytokine daily pain data streams design experience functional status health care service utilization improved intervention cost monocyte mortality multiplex assay neutrophil new therapeutic target novel strategies patient engagement peripheral blood phase III trial pilot trial primary outcome profiles in patients randomized placebo controlled trial randomized trial response sickling systemic inflammatory response treatment duration trend vascular injury

项目摘要

With the overall goal of understanding the mechanisms by which inhaled corticosteroids lead to systemic clinical benefits in individuals with Sickle Cell Disease (SCD) who do not have asthma, we have assembled a team of experts in hematology, pulmonology, immunology and SCD patient engagement with state-of-the-art capabilities for phenotyping pulmonary and systemic inflammation, vascular injury, functional status and patient reported outcomes. In SCD, sickling is caused by de-oxygenation of blood and reversed in the lung. Pulmonary inflammation interferes with re-oxygenation and potentiates further sickling, hemolysis, inflammation and vaso- occlusion. Over the last decade, our group and others demonstrated that pulmonary inflammation is present in SCD mice, that symptoms of episodic cough or wheeze (ECW) occur in half of SCD patients who do not meet criteria for a diagnosis of asthma and that ECW is a risk factor for increased SCD-related pain and death. In a pilot trial, inhaled steroids reduced systemic inflammation, hemolysis and daily pain with trends towards substantial reductions in healthcare utilization. Our global hypothesis is that inhaled steroids improve systemic inflammation and vascular injury in non-asthmatic SCD patients with ECW. To test this hypothesis, we will complete the following aims: AIM 1A: Compare pulmonary inflammation profiles in non-asthmatic SCD patients with and without ECW and, AIM 1B: Determine the effect of inhaled steroids on pulmonary inflammation in non-asthmatic SCD patients with ECW. AIM 2: Determine the effect of inhaled steroids on peripheral blood inflammatory and hemolytic signatures in non-asthmatic individuals with SCD and ECW. AIM 3: Establish a safety protocol for using inhaled steroids in an urban SCD clinical trial setting for 1 year. We will analyze induced sputum and blood using mass cytometry by time of flight (CyTOF - which has several advantages over flow cytometry) and multiplex assays, to define patterns of pulmonary and systemic inflammation that underlie the clinical phenomenon of ECW in SCD and to determine the effects of inhaled steroids on those inflammatory patterns. Once complete, we will use the knowledge gained to design a phase III trial of inhaled steroids for non-asthmatic individuals with SCD.

总体目标是了解吸入皮质类固醇导致全身性中毒的机制对于患有镰状细胞病（SCD）但没有哮喘的个体的临床益处，我们收集了由血液学、肺病学、免疫学和 SCD 患者组成的专家团队采用最先进的技术对肺部和全身炎症、血管损伤、功能状态和患者进行表型分析的能力报告的结果。在 SCD 中，镰状化是由血液脱氧引起的，并在肺部逆转。肺部炎症会干扰再氧合，并进一步加剧镰状化、溶血、炎症和血管生成。闭塞。在过去的十年中，我们的小组和其他人证明肺部炎症存在于 SCD 小鼠，不满足条件的 SCD 患者中有一半会出现阵发性咳嗽或喘息 (ECW) 症状哮喘诊断标准，ECW 是 SCD 相关疼痛和死亡增加的危险因素。在一个试点试验显示，吸入类固醇可减少全身炎症、溶血和日常疼痛，并有以下趋势：医疗保健利用率大幅下降。我们的总体假设是吸入类固醇可以改善全身系统 ECW 治疗非哮喘性 SCD 患者的炎症和血管损伤。为了检验这个假设，我们将完成以下目标： AIM 1A：比较非哮喘性 SCD 患者的肺部炎症情况有或没有 ECW 以及 AIM 1B：确定吸入类固醇对肺部炎症的影响采用 ECW 的非哮喘性 SCD 患者。目标 2：确定吸入类固醇对外周血液的影响患有 SCD 和 ECW 的非哮喘个体的炎症和溶血特征。目标 3：建立在城市 SCD 临床试验环境中使用吸入类固醇 1 年的安全方案。我们将分析使用飞行时间质谱流式细胞术（CyTOF）诱导痰液和血液（CyTOF - 与流式细胞术）和多重检测，以确定肺部和全身炎症的模式 SCD 中 ECW 的临床现象并确定吸入类固醇对这些症状的影响炎症模式。完成后，我们将利用获得的知识来设计吸入性药物的 III 期试验用于患有 SCD 的非哮喘患者的类固醇。