Positive Airway Pressure Gas Modulator - A Novel Method to Treat Central Sleep Ap

描述（由申请人提供）：睡眠呼吸暂停是一个主要的公共卫生问题，但传统的治疗方法主要集中在解决阻塞性睡眠呼吸暂停（OSA）上，如过多的气道正压、口腔器械等阻塞性治疗。然而，更多令人不安的睡眠呼吸暂停形式存在，比如那些由化学反射不稳定性介导的；然而，对这种疾病状态的治疗仍然不足。中枢性呼吸暂停和周期性呼吸是强化学反射介导睡眠呼吸暂停的典型多导睡眠图标志。最近，另一种被称为“复杂睡眠呼吸暂停”的变体被描述，其特征是在正压滴定期间持续诱导中枢呼吸暂停或严重的周期性呼吸，在诊断性多导睡眠图上似乎是一种阻塞性疾病。受影响的人群数量很大，仅复杂睡眠呼吸暂停一项估计就有150多万患者。我们建议开发一种新型气道正压设备，该设备将基于通过小心地维持二氧化碳（CO2）水平刚好高于二氧化碳依赖的呼吸暂停阈值来防止化学反射不稳定性。我们将这项技术称为：气道正压气体调节（PAPGAM）。我们已经进行了重要的初步实验，证明在应用气道正压治疗期间预防低碳酸血症可以使对当前治疗有抵抗力的患者恢复正常呼吸。第一阶段的总体目标是通过对更多患者进行多夜测试来确认PAPGAM的持续有效性和无毒性，而第二阶段将完成设备开发并进行广泛的临床试验。广泛的初步结果显示了相当高的安全性和有效性测试水平，再加上优秀的调查团队和项目的及时性，这些都鼓励我们提交快速通道申请，而不仅仅是第一阶段。第一阶段将评估具有化学反射依赖性睡眠呼吸暂停的受试者：1)在两周的时间内对PAPGAM的耐受性发展或缺乏。2) PAPGAM在血流动力学、呼吸、自主神经和代谢变量方面的安全性。二期将完成PAPGAM硬件和软件设计的开发，包括法规和医学标准测试，并进行广泛的中期疗效和毒性临床测试。我们相信，我们的方法将在睡眠呼吸障碍的治疗中创造一个范式转变，这将使有或没有严重合并症（如心力衰竭）的患者受益。我们的目标与美国国立卫生研究院对未来睡眠障碍研究的建议非常一致，这在最近的国家睡眠障碍研究中心计划中明确指出。我们已经召集了该领域的世界知名专家来执行这个项目。波士顿贝斯以色列女执事医疗中心的Robert Thomas博士和底特律韦恩州立大学医学院的Safwan Badr博士不仅是睡眠呼吸障碍领域的专家，而且是化学反射依赖性睡眠呼吸暂停这一新兴领域的领军人物。公共卫生相关性：睡眠呼吸暂停是一个主要的公共卫生问题，但传统的治疗方法主要集中在解决阻塞性睡眠呼吸暂停（OSA）上，如气道正压治疗、口腔器械治疗等。然而，更多令人不安的睡眠呼吸暂停形式存在，比如那些由化学反射不稳定性介导的；然而，对这种疾病状态的治疗仍然不足。中枢性呼吸暂停和周期性呼吸是强化学反射介导睡眠呼吸暂停的典型多导睡眠图标志。最近，另一种被称为“复杂睡眠呼吸暂停”的变体被描述，其特征是在正压滴定期间持续诱导中枢呼吸暂停或严重的周期性呼吸，在诊断性多导睡眠图上似乎是一种阻塞性疾病。受影响的人群数量很大，仅复杂睡眠呼吸暂停一项估计就有150多万患者。我们建议开发一种新型气道正压设备，该设备将基于通过小心地维持二氧化碳（CO2）水平刚好高于二氧化碳依赖的呼吸暂停阈值来防止化学反射不稳定性。我们将这项技术称为：气道正压气体调节（PAPGAM）。我们已经进行了重要的初步实验，证明在应用气道正压治疗期间预防低碳酸血症可以使对当前治疗有抵抗力的患者恢复正常呼吸。第一阶段的总体目标是通过对更多患者进行多夜测试来确认PAPGAM的持续有效性和无毒性，而第二阶段将完成设备开发并进行广泛的临床试验。广泛的初步结果显示了相当高的安全性和有效性测试水平，再加上优秀的调查团队和项目的及时性，这些都鼓励我们提交快速通道申请，而不仅仅是第一阶段。第一阶段将评估具有化学反射依赖性睡眠呼吸暂停的受试者：1)在两周的时间内对PAPGAM的耐受性发展或缺乏。2) PAPGAM在血流动力学、呼吸、自主神经和代谢变量方面的安全性。二期将完成PAPGAM硬件和软件设计的开发，包括法规和医学标准测试，并进行广泛的中期疗效和毒性临床测试。我们相信，我们的方法将在睡眠呼吸障碍的治疗中创造一个范式转变，这将使有或没有严重合并症（如心力衰竭）的患者受益。我们的目标与美国国立卫生研究院对未来睡眠障碍研究的建议非常一致，这在最近的国家睡眠障碍研究中心计划中明确指出。我们已经召集了该领域的世界知名专家来执行这个项目。波士顿贝斯以色列女执事医疗中心的Robert Thomas博士和底特律韦恩州立大学医学院的Safwan Badr博士不仅是睡眠呼吸障碍领域的专家，而且是化学反射依赖性睡眠呼吸暂停这一新兴领域的领军人物。

DESCRIPTION (provided by applicant): Sleep apnea is a major public health problem but traditional treatments have focused mostly on resolving obstructive sleep apnea (OSA) as demonstrated by the plethora of obstruction-motivated therapies like positive airway pressure, oral appliances, and others. However, more troubling forms of sleep apnea exist like those that are mediated by chemoreflex instability; yet, treatment for such disease states remain inadequate. Central apneas and periodic breathing are the classic polysomnographic markers of strong chemoreflex mediation of sleep apnea. Recently, another variation called "complex sleep apnea" has been described, which is characterized by sustained induction of central apneas or severe periodic breathing during positive pressure titration for what seems to be an obstructive disease on the diagnostic polysomnogram. The number of the affected population is large with Complex Sleep apnea alone estimated at over 1.5 million patients. We propose to develop a new class of positive airway pressure devices that will be based on preventing chemoreflex instability by carefully maintaining carbon dioxide (CO2) levels just above the CO2-dependent apneic threshold. We will call this technology: Positive Airway Pressure Gas Modulation (PAPGAM). We have conducted significant preliminary experiments demonstrating that prevention of hypocapnia during the application of positive airway pressure therapies can restore normal breathing to patients who were resistant to current therapies. The overarching goal of Phase I is to confirm the sustained efficacy and lack of toxicity of PAPGAM by testing more patients over multiple nights, while Phase II will complete device development and conduct an extensive clinical trial. The extensive preliminary results, which demonstrated an appreciable level of safety and efficacy testing combined with the excellent investigative team and timeliness of the project have encouraged us to submit a Fast Track application instead of Phase I only. Phase I will assess in subjects with chemoreflex dependent sleep apnea: 1) The development of tolerance, or lack of, to the PAPGAM over a two-week period. 2) The safety profile of the PAPGAM in relation to hemodynamic, respiratory, autonomic and metabolic variables. Phase II will complete the development of PAPGAM hardware and software design including regulatory and medical standards testing and conduct extensive medium term efficacy and toxicity clinical testing. We believe, our approach will create a paradigm shift in the treatment of sleep-breathing disorders that will benefit patients with and without significant comorbidities such as heart failure. Our goal is in strong agreement with NIH's recommendation for future sleep disorders research as clearly indicated in the most recent National Center for Sleep Disorders Research Plan. We have assembled world renowned experts in the field to execute this project. Dr. Robert Thomas from Beth Israel Deaconess Medical Center, Boston and Dr. Safwan Badr from Wayne State University School of Medicine, Detroit, are experts not only in the field of sleep disordered breathing but have been leading the emerging field of chemoreflex dependent sleep apnea. PUBLIC HEALTH RELEVANCE: Sleep apnea is a major public health problem but traditional treatments have focused mostly on resolving obstructive sleep apnea (OSA) as demonstrated by the plethora of obstruction-motivated therapies like positive airway pressure, oral appliances, and others. However, more troubling forms of sleep apnea exist like those that are mediated by chemoreflex instability; yet, treatment for such disease states remain inadequate. Central apneas and periodic breathing are the classic polysomnographic markers of strong chemoreflex mediation of sleep apnea. Recently, another variation called "complex sleep apnea" has been described, which is characterized by sustained induction of central apneas or severe periodic breathing during positive pressure titration for what seems to be an obstructive disease on the diagnostic polysomnogram. The number of the affected population is large with Complex Sleep apnea alone estimated at over 1.5 million patients. We propose to develop a new class of positive airway pressure devices that will be based on preventing chemoreflex instability by carefully maintaining carbon dioxide (CO2) levels just above the CO2-dependent apneic threshold. We will call this technology: Positive Airway Pressure Gas Modulation (PAPGAM). We have conducted significant preliminary experiments demonstrating that prevention of hypocapnia during the application of positive airway pressure therapies can restore normal breathing to patients who were resistant to current therapies. The overarching goal of Phase I is to confirm the sustained efficacy and lack of toxicity of PAPGAM by testing more patients over multiple nights, while Phase II will complete device development and conduct an extensive clinical trial. The extensive preliminary results, which demonstrated an appreciable level of safety and efficacy testing combined with the excellent investigative team and timeliness of the project have encouraged us to submit a Fast Track application instead of Phase I only. Phase I will assess in subjects with chemoreflex dependent sleep apnea: 1) The development of tolerance, or lack of, to the PAPGAM over a two-week period. 2) The safety profile of the PAPGAM in relation to hemodynamic, respiratory, autonomic and metabolic variables. Phase II will complete the development of PAPGAM hardware and software design including regulatory and medical standards testing and conduct extensive medium term efficacy and toxicity clinical testing. We believe, our approach will create a paradigm shift in the treatment of sleep-breathing disorders that will benefit patients with and without significant comorbidities such as heart failure. Our goal is in strong agreement with NIH's recommendation for future sleep disorders research as clearly indicated in the most recent National Center for Sleep Disorders Research Plan. We have assembled world renowned experts in the field to execute this project. Dr. Robert Thomas from Beth Israel Deaconess Medical Center, Boston and Dr. Safwan Badr from Wayne State University School of Medicine, Detroit, are experts not only in the field of sleep disordered breathing but have been leading the emerging field of chemoreflex dependent sleep apnea.