Regulatory Advancement of HXe as a Diagnostic MRI Contrast Agent

HXe 作为诊断 MRI 造影剂的监管进展

• 批准号: 8531325
• 负责人: Iulian Constantin Ruset
• 金额: $ 94.95万
• 依托单位: XEMED, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531325
• 关键词: Address; Aerosols; Agreement; Algorithms; Alveolar; Asthma; Biochemical; Bolus Infusion; Breathing; Caliber; Caring; Categories; Chest; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Contrast Media; Data; Data Analyses; Defect; Detection; Development; Devices; Diagnosis; Diagnostic; Diffusion; Dimensions; Disease; Dose; Duct (organ) structure; Environmental air flow; FDA approved; Gases; Glues; Goals; Health Care Costs; Helium; Histology; Image; Individual; Industry; Inhalation Device; Intervention; Investments; Label; Length; Location; Lung; Lung diseases; MRI Scans; Magnetic Resonance Imaging; Maps; Marketing; Measurement; Measures; Medical; Medical Device; Medical Imaging; Methods; Metric; Monitor; Obstructive Lung Diseases; Operative Surgical Procedures; Pathology; Patient Schedules; Patients; Pentetic Acid; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physiologic pulse; Physiological; Pilot Projects; Pleural cavity; Program Development; Protocols documentation; Protons; Provider; Pulmonary Emphysema; Pulmonary function tests; Quality of life; Quantitative Evaluations; Radionuclide Imaging; Reader; Reporting; Research; Respiratory physiology; Risk; Safety; Scanning; Services; Statistical Methods; Stents; Structure; System; Techniques; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Transplantation; United States Food and Drug Administration; Validation; Work; Xenon; commercialization; cost; cost effective; design; healthy volunteer; image processing; imaging modality; improved; in vivo; innovation; interest; lung volume; meetings; patient safety; prospective; prototype; research study; statistics; therapy development

DESCRIPTION (provided by applicant): New therapies are in development for COPD (endobronchial valves/stents/glue) and asthma (endobronchial thermal ablation). Hyperpolarized xenon-129 (HXe) MRI, a noninvasive method to assess regional lung structure and function, may prove critical in the guidance of these regional treatments. In our prior work we developed an innovative approach to xenon polarization that provides the liter quantities of highly polarized xenon-129 as required for medical imaging. Our prototype system was deployed at UVa where we performed 600 experiments in 64 patient and healthy volunteers and made significant advances in MR acquisition strategies and image quality. These promising results enable us to move to the next step in the commercialization of HXe, the performance of a Phase 2 clinical trial. Our goals for Phase 2 are to collect safety endpoints in patients with obstructive lung diseases, finalize the HXe dosing and MRI methods, and validate the HXe results by comparing with the existing clinical methods for assessing lung function and microstructure. We selected the two most mature and promising HXe techniques for inclusion in the Phase 2 trial: ventilation and diffusion imaging. Obstructive lung diseases such as COPD and asthma have been shown to have regional abnormalities of ventilation and these abnormalities are prime targets for intervention. Thus our first aim is to validate HXe MRI for the intended use of delineating ventilated and unventilated regions of the lung in COPD and asthma patients. For our Phase 2a trial we will compare HXe ventilation MRI and 99Tc DTPA ventilation scintigraphy (a clinical standard for assessing regional lung ventilation) in 10 healthy volunteers and 70 patients with COPD and asthma. In addition to the patient safety data, we will assess total lung volume and ventilated lung volume on MRI, and the congruence of ventilated volume boundaries between HXe MRI and scintigraphy. Recently completed pilot studies show that hyperpolarized helium diffusion imaging with six b-values can separately determine diffusion coefficients along and transverse to acinar ducts, which are related to alveolar depth and duct diameter. Our second aim is to validate HXe diffusion MR for the intended use of quantifying alveolar enlargement in emphysema, a fundamental abnormality that currently is assessed only by histology. For our Phase 2b trial we will perform diffusion HXe MRI in vivo in 18 COPD patients scheduled for lung transplant, and repeat the scan in the ex vivo lung after it is removed, thereby establishing that in vivo and ex vivo HXe measurements are concordant. The final step in the validation of the HXe diffusion measurement is to regionally compare alveolar size with morphometric measurements via histology from the explanted lung. The final portion of the proposed work is to raise quality to Phase 3 level, design a draft Phase 3 trial, meet with the FDA for a pre-Phase 3 meeting, and incorporate the FDA input into the Phase 3 protocol. The completion of the proposed work represents a significant advancement towards commercialization of HXe.

描述（由申请人提供）：COPD（支气管内瓣膜/支架/胶）和哮喘（支气管内热消融）的新疗法正在开发中。超极化氙-129 (HXe) MRI是一种评估局部肺结构和功能的无创方法，可能对这些局部治疗的指导至关重要。在我们之前的工作中，我们开发了一种创新的氙气偏振方法，可以提供医学成像所需的高偏振氙气-129的升量。我们的原型系统被部署在弗吉尼亚大学，在那里我们对64名患者和健康志愿者进行了600次实验，并在MR采集策略和图像质量方面取得了重大进展。这些有希望的结果使我们能够进入HXe商业化的下一步，即2期临床试验的表现。我们第2期的目标是收集阻塞性肺疾病患者的安全终点，最终确定HXe的剂量和MRI方法，并通过与现有临床评估肺功能和微观结构的方法进行比较来验证HXe结果。我们选择了两种最成熟和最有前途的HXe技术纳入二期试验：通气和扩散成像。阻塞性肺疾病如慢性阻塞性肺病和哮喘已被证明具有区域性通气异常，这些异常是干预的主要目标。因此，我们的第一个目标是验证HXe MRI在描绘COPD和哮喘患者肺部通气和不通气区域方面的预期用途。在我们的2a期试验中，我们将在10名健康志愿者和70名COPD和哮喘患者中比较HXe通气MRI和99Tc DTPA通气显像（评估局部肺通气的临床标准）。除了患者安全数据外，我们还将评估MRI上的总肺容量和通气肺体积，以及HXe MRI和显像之间通气体积边界的一致性。最近完成的初步研究表明，超偏振氦扩散成像具有6个b值，可以分别确定沿和横向的扩散系数，扩散系数与肺泡深度和导管直径有关。我们的第二个目的是验证HXe弥散MR用于量化肺气肿的肺泡扩大，这是一种目前仅通过组织学评估的基本异常。在我们的2b期试验中，我们将对18名计划进行肺移植的COPD患者进行体内弥散性HXe MRI，并在离体肺中重复扫描，从而确定体内和离体HXe测量值是一致的。验证HXe扩散测量的最后一步是通过外植肺的组织学将肺泡大小与形态学测量进行区域比较。建议工作的最后一部分是将质量提高到3期水平，设计3期试验草案，与FDA举行3期前会议，并将FDA的意见纳入3期方案。拟议工作的完成代表了HXe商业化的重大进展。