District of Columbia Childhood Asthma in Urban Settings - Clinical Research Center

哥伦比亚特区城市环境中的儿童哮喘 - 临床研究中心

• 批准号: 10210851
• 负责人: STEPHEN John TEACH
• 金额: $ 43.49万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210851
• 关键词: Allergens; Allergic; Antiviral Agents; Asthma; Bacteria; Basic Science; Bioinformatics; Biometry; Blood; Caring; Child; Childhood Asthma; Clinical; Clinical Data; Clinical Research; Computational Biology; Data; Disadvantaged; Disease; District of Columbia; Dose; Ecosystem; Epidemic; Event; Fostering; Future; Hour; Hypersensitivity; Immune response; Immunology; Infection; Inflammatory Response; Infrastructure; Institution; Institutional Review Boards; Interferon-alpha; Intervention; Investigational Drugs; Laboratories; Leadership; Microbe; Minority; Modeling; Molecular; Moraxella; Morbidity - disease rate; Nose; Obesity; Observational Study; Oral; Outcome; Participant; Patients; Pharmacy facility; Placebos; Production; Protocols documentation; Randomized; Randomized Clinical Trials; Research; Research Personnel; Research Project Grants; Rhinovirus; Risk; Role; Sampling; Schools; Seasons; Secure; Serum; Severities; Site; Streptococcus; Subcutaneous Injections; System; Time; Up-Regulation; Upper Respiratory Infections; Urban Community; Urban Population; Viral; Virus; Wheezing; Work; Youth; aged; allergic response; anti-IgE; asthma exacerbation; asthma prevention; atopy; base; cost; cytokine; data management; experience; falls; healthy volunteer; high risk; host microbiome; improved; inner city; innovation; metatranscriptome; microbiome; multidisciplinary; multiple omics; nasal microbiome; next generation; omalizumab; prevent; recruit; research study; respiratory microbiome; response; success; transcriptome; transcriptome sequencing; transcriptomics; urban children; urban setting

Leveraging our institution’s diverse and experienced investigator base, our success in leading collaborative and single-site randomized clinical trials (RCTs) and mechanistic and observational studies, and our access to a large population of urban, disadvantaged, and largely minority youth with asthma, we propose the District of Columbia’s Childhood Asthma in Urban Settings Clinical Research Center (DC CAUSE-CRC). It will implement network-wide research projects with a multi-disciplinary team of senior and junior investigators bringing diverse backgrounds in pediatric asthma, allergy and immunology, airway multi-omics, and computational biology. The proposed clinical leadership has repeatedly succeeded as top enrollers in multi-site asthma research collaboratives, and our institution houses the required infrastructure to facilitate CAUSE’s collaborative studies. For our site-specific project, we will build on the prior work of the Inner City Asthma Consortium (ICAC) and explore the mechanistic and clinical aspects of the paradigm-shifting use of a single dose of omalizumab in the fall season to prevent exacerbations. Specifically, while providing pilot clinical data for a possible future RCT, we will examine the interaction of the nasal microbiome and the nasal inflammatory responses during viral upper respiratory infections (URIs) with and without a single dose of anti-IgE. Working synergistically in exacerbation-prone urban youth, allergic sensitization, allergen exposure, and rhinovirus (and other viral) URIs trigger a strong Th2 response and asthma exacerbations that occur most frequently after school begins (the “September epidemic”). The ICAC has demonstrated that when administered across the entire fall season, omalizumab reduces the odds of exacerbations by >50%. Given the cost and complexity of this approach, however, and noting that serum levels of omalizumab rise following subcutaneous injection within a time frame sufficient to prevent a virally induced exacerbation (7-8 days), we propose an entirely new strategy: Omalizumab Before Onset of Exacerbations (OBOE). It is a pilot, non-therapeutic, mechanistic RCT of omalizumab or placebo administered within 72 hours of onset of an URI. Over three fall seasons, OBOE will randomize at least 100 youth aged 6-17 years with persistent asthma, high atopy, and a recent exacerbation. We will “capture” their URIs for 90 days after school starts, sampling their nasal airways twice (within 72 hours of URI onset and again in a window between 7-10 days after URI onset). Our specific aims are: (1) to be leaders in the collaborative studies of the CAUSE network while fostering the next generation of local institutional leadership for DC CAUSE-CRC; (2) to determine the relationship among the nasal airway microbiome, host transcriptome, and Th2 responses in children treated with single dose omalizumab or placebo at the onset of viral URIs; (3) to determine the relationship between host nasal airway antiviral interferon-α response with and without omalizumab given at the onset of a viral URI; and (4-exploratory): to determine the differences in clinical outcomes between intervention and control participants.

利用我们机构多元化且经验丰富的研究人员基础，我们在领导协作方面取得了成功 和单中心随机临床试验（RCT）以及机制和观察性研究，以及我们对 由于大量城市人口、弱势群体和大多数少数民族青年患有哮喘，我们建议设立 哥伦比亚城市环境儿童哮喘临床研究中心 (DC CAUSE-CRC)。它将实施 网络范围内的研究项目，由高级和初级研究人员组成的多学科团队带来多样化 拥有小儿哮喘、过敏和免疫学、气道多组学和计算生物学的背景。这 拟议的临床领导力多次成功成为多中心哮喘研究的顶级招募者 我们的机构拥有促进 CAUSE 合作研究所需的基础设施。 对于我们的特定地点项目，我们将以内城哮喘联盟 (ICAC) 之前的工作为基础， 探索单剂量奥马珠单抗在治疗中的范式转变使用的机制和临床方面 秋季应预防病情加重。具体来说，在为未来可能的随机对照试验提供试点临床数据的同时， 我们将研究病毒感染期间鼻腔微生物组和鼻腔炎症反应的相互作用 使用或不使用单剂抗 IgE 的上呼吸道感染 (URI)。协同工作 易加重的城市青年、过敏性致敏、过敏原暴露和鼻病毒（和其他病毒）URI 引发强烈的 Th2 反应和哮喘恶化，最常在开学后发生（ 《九月疫》）。 ICAC 已经证明，在整个秋季实施时， 奥马珠单抗可将病情加重的几率降低 50% 以上。考虑到这种方法的成本和复杂性， 然而，并注意到皮下注射后一段时间内奥马珠单抗的血清水平上升 足以预防病毒引起的病情加重（7-8天），我们提出了一个全新的策略： 病情加重前的奥马珠单抗 (OBOE)。这是一项试验性、非治疗性、机制性随机对照试验 URI 发病后 72 小时内给予奥马珠单抗或安慰剂。在三个秋季季节里，双簧管将 随机抽取至少 100 名 6-17 岁患有持续性哮喘、高度特应性且近期病情加重的青少年。 我们将在开学后 90 天内“捕获”他们的 URI，对他们的鼻呼吸道进行两次采样（72 小时内） URI 发病后的 7-10 天的窗口内再次）。我们的具体目标是：（1） CAUSE网络合作研究的领导者，同时培养下一代当地 DC CAUSE-CRC 的机构领导； (2)确定鼻气道之间的关系 使用单剂量奥马珠单抗或单剂量治疗的儿童的微生物组、宿主转录组和 Th2 反应 病毒性 URI 发作时服用安慰剂； (3)确定宿主鼻气道抗病毒的关系 在病毒性 URI 发作时给予或不给予奥马珠单抗的干扰素-α 反应；和（4-探索性）： 确定干预参与者和对照参与者之间临床结果的差异。