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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性皮质类固醇导致全身性没有哮喘的镰状细胞病（SCD）患者的临床益处，我们已经组装了一个血液学、肺病学、免疫学和SCD患者参与的专家团队，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，并在肺中逆转。肺炎症干扰再氧合并进一步增强镰状化、溶血、炎症和血管- 闭塞在过去的十年里，我们的团队和其他人证明了肺部炎症存在于 SCD小鼠，发作性咳嗽或喘息（ECW）的症状发生在一半的SCD患者中，哮喘的诊断标准，并且ECW是SCD相关疼痛和死亡增加的风险因素。中试点试验，吸入类固醇减少全身炎症，溶血和日常疼痛的趋势，医疗保健利用率大幅下降。我们的总体假设是，吸入类固醇改善全身 ECW治疗非哮喘性SCD患者炎症和血管损伤。为了验证这个假设，我们将完成以下目标：目的1A：比较非哮喘性SCD患者的肺部炎症特征有和没有ECW和AIM 1B：确定吸入类固醇对肺炎症的影响，患有ECW的非哮喘性SCD患者。目的2：确定吸入类固醇对外周血的影响在患有SCD和ECW的非哮喘个体中的炎症和溶血特征。目标3：建立在城市SCD临床试验环境中使用吸入性类固醇1年的安全性方案。我们将分析使用飞行时间质谱细胞术（CyTOF）诱导痰和血液，流式细胞术）和多重测定，以确定肺和全身炎症的模式， SCD中ECW的临床现象，并确定吸入类固醇对这些现象的影响。炎症模式一旦完成，我们将利用所获得的知识来设计一个吸入性的III期试验。类固醇用于患有SCD的非哮喘个体。