A Naloxone Parachute: Novel Wearable Dual-Sensor Regional Oximeter to Detect Opioid-Induced Hypoxia and Enable Emergent Naloxone Rescue

摘要 美国已经失去了50万美国人的阿片类药物流行病;每天超过125人死亡 在2018年。纳洛酮是第一反应者逆转阿片类药物过量（OD）的标准治疗， 美国卫生局局长提倡旁观者使用。然而，许多致命的OD发生时， 是孤独的迫切需要新的阿片类药物过量检测和逆转方法， 旁观者的干预。纳洛酮降落伞是一种组合药物器械产品， 组件：用于检测过量的可穿戴生物传感器（ERDx）和可穿戴的器械激活自动注射器 自动输送救援剂量的盐酸纳洛酮该装置可以降低致命过量的风险， 阿片类药物使用对公众健康的影响。 该生物传感器，紧急呼吸诊断（ERDx）设备，包含多个医疗级 血氧计监测生命体征和独立的蜂窝调制解调器（不需要电话）联系帮助。这 一种新的设备是第一个使用两个PPG和一个NIRS独立血氧仪来检测呼吸暂停和缺氧， 临床相关性，并在“智能”器械逻辑中利用它们来确定是否存在危及生命的过量用药。 怀疑并需要干预。干预措施包括呼叫指定的帮助，声音警报， 最终激活装置介导的纳洛酮拯救。 本I期研究将评价新型ERDx器械以及市售ERDx器械的性能。 在气体诱导缺氧至70%的条件下，在人类受试者中使用局部血氧计，然后使用阿片类药物 （瑞芬太尼）诱导的呼吸暂停伴缺氧至80%。还将收集传感器功能和纳洛酮PK/PD数据。 在本研究中，由临床工作人员给药，在三角肌肌内（IM）纳洛酮恢复后获得。 这些数据将为未来的研究奠定基础，当我们测试与新型可穿戴设备集成的ERDx时， 连接IM自动注射器，由Ayuda单独开发。 我们的目标是证明躯体（手臂，腿，躯干）传感器血氧测定与手指相关 在气体诱导和阿片样物质诱导的缺氧期间的脉搏血氧测定和动脉血气（ABG）控制。我们 旨在评价两种光学血氧饱和度传感器类型光电体积描记术（PPG）检测的准确性 和近红外光谱（NIRS）在一系列控制的高原条件下温和（85-89%）， SaO_2）、中度（80- 84%SaO_2）和重度（<80%SaO_2）缺氧。进一步的目标是衡量 瑞芬太尼的药代动力学和药效学（PK/PD），包括诱导呼吸暂停/缺氧， 纳洛酮1- 2 mg IM的PK/PD和其逆转症状的能力。我们还打算要求早日 与FDA举行合作会议，讨论ERDx和纳洛酮降落伞的监管路径 设备，并在未来的研究中使用瑞芬太尼-纳洛酮方法作为阿片类药物过量模型。

ABSTRACT The United States has lost 500,000 Americans to the Opioid Epidemic; over 125 people died each day in 2018 alone. Naloxone is the standard of care for first-responders to reverse opioid overdose (OD), and its use by bystanders is advocated by the US Surgeon General. However, many fatal OD occurs when subjects are alone. There is an urgent need for new opioid overdose detection and reversal methods that do not rely upon bystanders to intervene. The Naloxone Parachute is a combination drug-device product with two key components: a wearable biosensor (ERDx) to detect overdose and a wearable, device-activated, autoinjector to automatically deliver a rescue dose of naloxone HCl. This device can reduce the risk of fatal overdose and the public health impact of opioid use. The biosensor, the Emergency Respiratory Diagnostic (ERDx) device, contains multiple medical-grade oximeters to monitor vital signs and stand-alone cellular modem (no phone necessary) to contact help. This novel device is the first to use two PPG and a NIRS independent oximeters to detect apnea and hypoxia with clinical relevance, and utilize them in “intelligent” device logic to determine if life-threatening overdose is suspected and intervention is required. Intervention includes calling designated help, audible alert, and eventually activating the device-mediated naloxone rescue. This Phase I study will evaluate the performance of the novel ERDx device as well as commercial regional oximeters in Human Subjects under conditions of gas induced hypoxia to 70%, and then opioid (remifentanil)-induced apnea with hypoxia to 80%. Sensor function and Naloxone PK/PD data will also be obtained following deltoid intramuscular (IM) naloxone recovery, in this study administered by clinical staff. This data will lay the groundwork for future studies when we test the ERDx integrated with a novel wearable connected IM autoinjector, which is being developed separately by Ayuda. Our objectives are to demonstrate that somatic (arm, leg, trunk) sensor oximetry correlates with finger pulse oximetry and arterial blood gas (ABG) controls during gas induced and opioid induced hypoxia. We intend to evaluate the accuracy of detection of two optical oximetry sensor types photoplethysmography (PPG) and near-infrared spectroscopy (NIRS) in a series of controlled plateaus under conditions of mild (85-89% SaO2), moderate (80-84% SaO2) and severe (<80% SaO2) hypoxia. Further objectives are to measure pharmacokinetics and pharmacodynamics (PK/PD) of remifentanil including the induction of apnea/hypoxia, and PK/PD of Naloxone 1-2mg IM and its ability to reverse symptoms. We also intend to request an Early Collaboration meeting with the FDA to discuss the regulatory path for the ERDx and Naloxone Parachute devices, and the use of the remifentanil-naloxone approach as an opioid overdose model in future studies.