Assessment of lung function in neonates and infants

 描述(申请人提供)：虽然肺部疾病是儿童发病的主要原因，但评估疾病所需的强迫呼吸动作，肺活量测定，不能由幼儿进行。因此，根据父母的报告，描述儿童肺部疾病的活动性或监测儿童肺部疾病的严重程度主要是定性的，几乎没有量化信息来作为治疗决定的基础。同样重要的是，在没有可量化的结果衡量标准的情况下，很难对患有肺部疾病的幼儿进行临床试验。超极化氦-3(HHE)磁共振成像(MRI)是一种高灵敏度、多用途、高分辨率的肺功能微结构断层扫描(3D)定量成像方法。表观弥散系数(ADC)是反映肺泡长度尺度的影像生物标志物，它可以判断早产儿的分期和/或评估与慢性早产儿肺疾病相关的间隔壁的损伤。由于HHE MRI是非电离的，婴儿和儿童将从这一新出现的诊断模式中受益最多。在第一阶段，我们开发和展示了新的设备、方法和技术，并从11名9个月至3岁的自由呼吸、未服用镇静剂的婴儿身上获取了HHE MRI图像，确立了无需语音吸入和屏气指令进行成像的可行性。对于第二阶段，我们建议进行临床研究、技术改进和监管申报，以推动HHE MRI走向新药应用。在目标1中，我们将进行一项简单的纵向试验，招募8名患有BPD的早产儿。我们将在NICU进行第一次成像，并在校正后的6个月时再次成像。我们还将招募8名足月婴儿，并在1岁和6岁时进行成像 月份。这第二个队列将作为牙槽大小正常发育的年龄匹配的对照。我们将探讨HHE MRI扩散敏感成像是对新生儿肺泡大小的敏感和特异性评估，区分异常和正常和分层严重程度的假设。在目标2中，我们将完善基础设施技术，并为新生儿肺功能评估所需的所有基本组件和方法建立最终规范，包括HHE偏振器、气体给药设备(S)、新生儿大小的胸腔线圈、快速螺旋成像脉冲序列和数据分析软件。在AIM#3中，我们将提交FDA关于HHE作为诊断药物用于评估新生儿肺功能微结构的法规文件。我们还将提交监管文件，以提前FDA批准我们用于NICU的设备。BPD被认为是一种孤儿疾病，这减轻了HHE被批准为该疾病人群的新药的监管负担。

 DESCRIPTION (provided by applicant): Although lung disease is a major cause of morbidity in children, the forced breathing maneuvers required for assessing disease, spirometry, cannot be performed by young children. Thus, characterizing the activity or monitoring the severity of pediatric lung disease in younger children is primarily qualitative, based upon parental reports, with little quantitative information upon which to base treatment decisions. Equally important, it is difficult to perform clinical trials in young children with lung disease in the absence of a quantifiable outcome measure. Hyperpolarized helium-3 (HHe) magnetic resonance imaging (MRI) is an exquisitely sensitive, versatile, and quantitative modality for tomographic (3D) mapping of pulmonary functional microstructure with excellent resolution. The Apparent Diffusion Coefficient (ADC), an imaging biomarker for alveolar length-scales, can determine the stage of prematurity and/or assess injury to septal walls associated with chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Because HHe MRI is non-ionizing, infants and children stand the most to benefit from this newly emerging diagnostic modality. During Phase I we developed and demonstrated new devices, methods, and technology and acquired HHe MRI images from eleven free-breathing, unsedated infants between the ages of nine months and three years, establishing feasibility for imaging without voice inhalation and breath-hold commands. For Phase II we propose clinical studies, technical refinements, and regulatory filings that will advance HHe MRI towards a New Drug Application. In Aim#1 we will conduct a simple longitudinal trial, recruiting eight preterm infants with BPD. We will perform the first imaging session in the NICU and image again at six months corrected gestational age. We will also recruit a cohort of eight full-term infants, and image at one and six months. This second cohort will serve as an age-matched comparator for normal development of alveolar dimension. We will investigate the hypothesis that HHe MRI diffusion-sensitive imaging is a sensitive and specific assessment of alveolar dimension in neonates, distinguishing abnormal from normal and stratifying severity. In Aim#2 we will refine the infrastructure technology and establish a final specification for all essential components and methods required for neonatal lung function assessments including the HHe polarizer, gas administration device(s), neonatal-sized chest coil, fast spiral imaging pulse sequences, and data analysis software. In Aim#3 we will submit regulatory filings for FDA advancement of HHe as a diagnostic drug agent for assessments of lung functional microstructure in neonates. We will also submit regulatory filings to advance the case for FDA approval of our devices for the NICU. BPD is considered an orphan disease, which eases the regulatory burden for approval of HHe as a New Drug for this disease population.