Regional monitoring of CF lung disease after changes in mechanical airway-clearance treatment

机械气道清除治疗改变后 CF 肺部疾病的区域监测

• 批准号: 10737221
• 负责人: Raouf S. Amin
• 金额: $ 80.24万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737221
• 关键词: Address; Adolescent and Young Adult; Adult; Affect; Bicarbonates; Bronchiectasis; Child; Chlorides; Chronic; Clinical Trials; Communities; Community Surveys; Consumption; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dedications; Defect; Effectiveness; Ethics; Family; Frequencies; Functional Magnetic Resonance Imaging; Gases; Genes; Goals; Hour; Infection; Inflammation; Ion Transport; Ionizing radiation; Lung; Lung diseases; Magnetic Resonance Imaging; Maintenance; Maintenance Therapy; Measurement; Mechanics; Medical; Modality; Monitor; Mucociliary Clearance; Mucous body substance; Mutation; Obstruction; Patient risk; Patients; Persons; Population; Progressive Disease; Prospective Studies; Proteins; Provider; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Ventilation; Pulmonary function tests; Risk; Safety; Severities; Specificity; Spirometry; Structural defect; Structure; Structure-Activity Relationship; Surveys; Systemic disease; Techniques; Testing; Time; Tissues; United States; Volition; Withdrawal; X-Ray Computed Tomography; aged; clinical care; cystic fibrosis patients; effective therapy; effectiveness evaluation; lung imaging; lung injury; member; novel therapeutics; pulmonary function; pulmonary function decline; structural imaging; tool; treatment response; ventilation

PROJECT SUMMARY Cystic fibrosis (CF) is a progressive disease affecting around 30,000 people in the US and is caused by a mutation in a gene affecting the CFTR protein that regulates mucus composition. In airways in the lung this leads to mucus stasis, infection, and remodeling that result in mucus plugs, poor ventilation, and progressive airway destruction. Highly-effective CFTR modulators, now available to >90% of patients, have revolutionized clinical care, with increases in pulmonary function via more effective mucociliary clearance. Burdensome maintenance therapies like airway clearance treatment (ACT) require around 2 dedicated hours per day and have been questioned by patients, families, and medical providers. In a recent CF-community survey, airway clearance was ranked as the most burdensome therapy. Traditional studies of therapy withdrawal pose some patient risk, since measurement is via relatively insensitive pulmonary function testing (PFT) and lung-function reductions can have permanent consequences. Breakthroughs in structural and hyperpolarized-gas MRI demonstrate exquisite sensitivity to CF lung disease and can be used to monitor regional and subtle changes over time, much more precisely than PFTs, and with regional specificity. MRI provides a unique opportunity to safely evaluate ACT. The overarching goal of our proposal is to determine effectiveness of ACT in the era of highly effective CFTR modulators by studying structure-function relationships via MRI in patients of varying severity who have stopped and restarted ACT. We will achieve this goal via three separate, hypothesis-driven Aims in this clinical trial: Hypothesis 1: Patients who have relatively low structural defects will have fewer ventilation defects and higher pulmonary function, and these defects will relate to frequency of ACT usage. Specific Aim 1: To perform UTE and hyperpolarized Xe MRI in 30 CF patients aged 12-21, approximately 15 of whom have self-withdrawn ACT, to regionally characterize obstructive severity and correlate regional structural lung abnormalities (via UTE FLORET MRI) to functional deficits (via Xe MRI) Hypothesis 2: Patients who have self-withdrawn ACT after initiation of effective modulators will demonstrate increases in regional ventilation after reinitiating treatment, with greater ventilation increases in patients with a higher level of lung abnormalities. Specific Aim 2: To perform a stepwise ACT re-initiation trial in fifteen 12-21 y.o. patients who have self-withdrawn airway clearance treatment (defined as ≤ 3x/week). UTE and Xe MRI, spirometry, and multiple-breath washout will be performed at baseline, after increasing treatment to 7x/week for 1 week and then 14x/week for 2 weeks, with daily logging to aid compliance and study engagement. Hypothesis 3: Patients who currently use 2x daily ACT and have few lung abnormalities on MRI can reduce to 1x daily or less, with no significant functional changes in the lung. Specific Aim 3: To perform a stepwise ACT withdrawal trial in fifteen 12-21 y.o. patients who have low MRI abnormalities and high FEV1. Patients will be studied at baseline, after decreasing ACT to 7x/wk for 1 week, and after decreasing ACT to 3x/wk for 1 week.

项目摘要 囊性纤维化（CF）是一种进展性疾病，影响了美国约30,000人，是由 影响调节粘液组成的CFTR蛋白的基因中的突变。在肺的气道中 粘液停滞，感染和重塑，导致粘液塞，通风不良和渐进气道 破坏。现已在90％的患者中使用的高效CFTR调节剂已彻底改变了临床 护理，通过更有效的粘膜缩减清除率增加了肺功能。繁重的维护 诸如气道通关疗法（ACT）之类的疗法每天需要大约2个专用小时 受患者，家庭和医疗提供者的讯问。在最近的CF社区调查中，气道通关是 被评为最生育的疗法。传统的治疗戒断研究构成了一些患者的风险，因为 测量是通过相对不敏感的肺功能测试（PFT）和肺部功能降低的方法 永久后果。结构性和超极化气体MRI的突破性表现出独家 对CF肺部疾病的敏感性，可用于监测随着时间的时间和微妙的变化，更多 与PFT相比，具有区域特异性。 MRI提供了一个独特的机会来安全评估行为。 我们提案的总体目标是确定在高效CFTR时代的行为有效性 通过MRI研究结构功能关系的调节剂，以不同严重程度的患者停止 并重新开始行为。在这项临床试验中，我们将通过三个单独的假设驱动的目标来实现这一目标： 假设1：结构缺陷相对较低的患者的通气缺陷将更少，较高 肺功能，这些缺陷将与ACT使用频率有关。特定目标1：执行UTE 在30名12-21岁的CF患者中，超极化的XE MRI，其中约15例具有自我处理ACT， 区域表征阻塞性严重程度并相关的区域结构肺异常（通过UTE 小花MRI）到功能性缺陷（通过XE MRI） 假设2：启动有效调节剂后具有自我掌握的行为的患者将证明 重新启动治疗后，区域通风增加，患者的通气增加增加 较高的肺部异常。特定目的2：在15个12-21中进行逐步ACT重新生效试验 Y.O.具有自动气道通量治疗（定义为≤3倍/周）的患者。 Ute和Xe MRI， 在将治疗的治疗增加到7倍/周后，将在基线上进行肺活量测定法和多呼吸。 1周，然后每周14倍/周，每天记录以帮助合规和学习参与。 假设3：目前使用2倍每日法且在MRI上肺异常的患者可以减少到 每天或更少1倍，肺部没有显着的功能变化。特定目标3：执行逐步行动 撤回审判在15个12-21 Y.O. MRI异常和高FEV1的患者。患者会 在基线时进行了研究，在将ACT降低到7倍/周后，持续了1周，在将ACT降低到3倍/周后，持续了1周。