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.

项目概要 囊性纤维化 (CF) 是一种进行性疾病，影响美国约 30,000 人，由以下疾病引起： 影响调节肺部气道粘液成分的 CFTR 蛋白的基因发生突变。 粘液淤滞、感染和重塑，导致粘液栓、通气不良和渐进性气道 高效的 CFTR 调节剂现已可供超过 90% 的患者使用，彻底改变了临床。 护理，通过更有效的粘液纤毛清除来增强肺功能。 气道清除治疗 (ACT) 等疗法每天需要大约 2 个小时的专门时间，并且已 在最近的一项 CF 社区调查中，气道清理受到患者、家属和医疗服务提供者的质疑。 被认为是最繁琐的治疗方法，因为传统的治疗戒断研究会给患者带来一些风险。 测量是通过相对不敏感的肺功能测试（PFT）进行的，肺功能下降可能会导致 结构和超极化气体 MRI 的突破证明了其深远的影响。 对 CF 肺部疾病的敏感性，可用于监测随时间的区域和细微变化，等等 MRI 比 PFT 更精确，并且具有区域特异性，为安全评估 ACT 提供了独特的机会。 我们提案的总体目标是确定 ACT 在高效 CFTR 时代的有效性 通过 MRI 研究已停止治疗的不同严重程度患者的结构与功能关系来调节调节剂 并重新启动 ACT 在此临床试验中通过三个独立的、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通气缺陷较少且较高 肺功能，这些缺陷将与 ACT 使用频率相关。具体目标 1：进行 UTE。 对 30 名 12-21 岁的 CF 患者进行超极化 Xe MRI，其中大约 15 名患者已自行撤回 ACT， 区域性描述阻塞严重程度并关联区域性肺结构异常（通过 UTE FLORET MRI）到功能缺陷（通过 Xe MRI） 假设 2：在开始有效调节剂后自行撤回 ACT 的患者将表现出 重新开始治疗后局部通气量增加，患有以下疾病的患者通气量增加幅度更大 具体目标 2：在 12-21 15 日进行逐步 ACT 重新启动试验。 接受自行撤回气道清除治疗的患者（定义为每周 3 次 UTE 和 Xe MRI）。 将治疗次数增加至每周 7 次后，将在基线时进行肺活量测定和多次呼吸冲洗 1 周，然后每周 14 次，持续 2 周，每天记录以帮助依从性和研究参与度。 假设 3：目前每天使用 2 次 ACT 且 MRI 上肺部异常很少的患者可以减少至 每天 1 次或更少，肺部无明显功能变化 具体目标 3：执行逐步 ACT。 对 15 名 MRI 异常低且 FEV1 较高的患者进行戒断试验。 在基线时、将 ACT 减少至 7 次/周持续 1 周后以及将 ACT 减少至 3 次/周持续 1 周后进行研究。