SBIR-STTR Award

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.

Public Health Relevance Statement:
2020-04 Naloxone Parachute: Novel Wearable Dual Sensor Regional Oximeter to Detect Opioid-Induced Hypoxia and Enable Emergent Naloxone Rescue NARRATIVE: We are developing a wearable opioid overdose intervention by decreasing time to recognition of critical event, time to notification for help, and time to Naloxone administration. A discreet biosensor device that utilizes several oximeters, detects low breathing rate and oxygenation, and wirelessly (no phone necessary) alerts is a fundamental improvement in patient safety, enabling patients to be rescued from overdose even when they are alone. A wearable intramuscular Naloxone device will remove bystander barriers to administration (e.g. diagnosis and treatment decision, fear of needles, interaction with an unconscious patient, body fluid exposure), and can increase Naloxone access among populations most vulnerable to accidental opioid overdose including people who are in recovery, have a history of overdose, or are recently justice-system involved thus significantly decreasing the public health impact of Opioid Use Disorder.

Project Terms:
Apnea; Breathing; Respiratory Aspiration; Respiratory Inspiration; inspiration; Body Fluids; Modems; Dataphones; Diagnosis; Drug Combinations; Drug Modelings; Emergency Situation; Emergencies; Equipment; Fright; Fear; Fingers; Future; Gases; Gold; Recording of previous events; History; Intravenous infusion procedures; IV Infusion; intravenous infusion; Intramuscular Injections; intramuscular drug administration; Intelligence; Justice; Light; Photoradiation; Logic; Methods; Naloxone; Needles; Nitrogen; Optics; optical; Overdose; Oxygen; O element; O2 element; Parachuting; Patients; Public Health; Pulse Oximetry; Research; Risk; Safety; San Francisco; Telephone; Phone; Testing; Time; Unconscious State; Unconscious; Unconsciousness; consciousness loss; United States; Measures; Mediating; Blood gas; Light Reflection Rheography; Photoreflexometries; Photoreflexometry; Photoplethysmography; human subject; sensor; Anterior; Clinical; Phase; Medical; Series; Ensure; Evaluation; Deltoid; deltoid muscle; Recovery; Hypoxic; Oxygen Deficiency; Hypoxia; cerebral; Cerebrum; Opiates; Opioid; remifentanil; Collaborations; Diagnostic; NIR Spectroscopy; Near-Infrared Spectrometry; Near-Infrared Spectroscopy; Life; Pulse; Physiologic pulse; Notification; Investigation; Event; Intramuscular; Protocol; Protocols documentation; Upper arm; System; Location; respiratory; Oximetry; Oxygen saturation measurement; meetings; Surgeon; American; monitoring device; Performance; success; biological sensor; Biosensor; novel; Devices; Deterioration; Modeling; Intervention Strategies; interventional strategy; Intervention; Manufacturer; Manufacturer Name; patient safety; Leg; Dose; Symptoms; Advocate; Data; Detection; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; wireless; Wireless Technology; Monitor; Authorization; Permission; Authorization documentation; developmental; Development; emergency personnel; emergency responder; emergency service personnel; emergency service responder; clinical site; clinical research site; Population; clinical relevance; clinically relevant; standard of care; Phase I Study; phase 1 study; arm; IRB; IRBs; Institutional Review Boards; opiate use disorder; opioid use disorder; opiate consumption; opiate drug use; opiate intake; opiate use; opioid consumption; opioid drug use; opioid intake; opioid use; opiate crisis; opioid crisis; opioid epidemic; opiate overdose; opiate related overdose; opioid drug overdose; opioid induced overdose; opioid intoxication; opioid medication overdose; opioid poisoning; opioid related overdose; opioid toxicity; opioid overdose; wearable electronics; wearable technology; wearable device; Inhaling; Inhalation; first responder; PK/PD; pharmacokinetics and pharmacodynamics

SBIR PHASE II - Ayuda Medical has the vision that no-one should die from a treatable medical emergency. Opioid overdoses (OODs) are treatable with basic CardioPulmonary Resuscitation (CPR), but they claimed over 250 lives each day in the US in 2020. Patients most at risk for OOD are people in treatment for Opioid Use Disorder (OUD) or High Impact Chronic Pain (HICP). The current standard of care to OOD is bystander response (medical or nonmedical), but the bystander needs to know that an OOD is occurring. We present a wearable medical diagnostic device to detect OOD and bridge the gap to bystander intervention. Our device, Parachute ARMband, will be worn continuously, and will monitor physiologic parameters that indicate OOD, then will use an on-device escalating tonal alarm to summon bystanders, as well as on- device speaker to verbally identify the urgency to get medical help. No wireless connectivity is required for these functions. The ARMband will also send a Bluetooth alert to an adjunct Mobile Medical Application (MMA) on the User's phone, that can reach designated contacts, previously chosen by the device user. This function requires mobile device connectivity, and that the MMA be downloaded prior to the medical event. Company has completed a Phase I SBIR, sponsored by National Institute of Drug Abuse (NIDA), that showed the upper arm is a viable location for wearable oximeters, main components of novel device. The addition of Phase I Innovation Corps enabled company to validate Minimal Viable Product (MVP) key features, including escalating alarm and wireless alert. Together our Phase I learnings allowed Principle Investigator (PI) to submit a Breakthrough Device Designation (BDD) request to the FDA. This proposed Phase II application will show feasibility of our novel device components to detect gas- induced hypoxia, compared to arterial blood gas (Aim 1); sensitivity of device to detect intravenous remifentanil "OOD" and begin alarm algorithm (Aim 2); and ability of device communications to send a real-time wireless alert (Aim 3). These three aims support device safety and effectiveness. In Aim 4, Human Factors and Instructions for Use (IFU) are specifically tested in our target population, persons with a history of OUD or OOD. Aim 5 likewise tests the device in our target population, but also adds our target use environment; it will test device's wearability via 48hr and and two-to-four week take home studies. Together all five Aims, along with non-clinical testing of device design and alarms, will support seeking Class II marketing via a De Novo submission, with the device indicated for People Who Use Opioids (PWUOs) including HICP, and people with a history of OUD that are at risk for OOD. To date there is no FDA approved device to monitor for OOD. We offer a continuous monitor because stressors and triggers to opioid use can be unexpected. The De Novo submission will include data from studies designed for our target clinical scenario (acute opioid ingestion/ administration), and target use environment (ambulatory, at-home). Ayuda Medical plans to have several discussions with the United States Food and Drug Administration (FDA), throughout device development and Phase II. BDD was submitted in Q3, 2021, and company plans to submit a Q-sub clarifying our milestones to approval in Q4, 2021. We plan to use early gas hypoxia studies (Aim 1A) to apply for Investigational Device Exemption (IDE), and then perform clinical studies with opioid- specific protocols (Aims 2 and 3). This includes feasibility (Q4, 2022) and pivotal (Q4, 2023) studies sponsored by Phase II. Continuous interactions with FDA will align company milestones with FDA objectives. Commercialization strategy includes seeking federal Medicaid coverage in tandem with FDA approval, as part of a dual-panel (FDA-CMS) pre-marketing review. Company plans to market the ARMband directly within the OUD market, and co-market the device with a strategic partner within the HICP market. We also intend to conduct community-based pilot studies in collaboration with NIDA and the Substance Abuse and Mental Health Services Administration (SAMHSA), to validate device system in specific to the OUD/HICP populations in target environment, and to support formulary inclusion by State Medicaid. State Medicaid coverage assures that the device is affordable and accessible by Community Health Centers (CHCs), that treat the majority of the low-income populations for both chronic and acute illnesses, including OUD and OOD. Establishing a viable commercial path via state Medicaid and CHCs, that can then be expanded into 50 states, is an attractive proposal to partnerships and potential exit companies in the OUD market. Phase I validated device need and feasibility of our development approach. Phase II will provide the appropriate clinical and non-clinical testing to support a De Novo submission to the FDA. Company is fully dedicated to the approval and commercialization of the Parachute ARMband OOD diagnostic device, and to making it available to all at-risk groups, aiming to expand the protection against accidental opioid overdose.

Public Health Relevance Statement:
2021 09, Hite, Naloxone Parachute: Novel Wearable Dual Sensor Regional Oximeter to Detect Opioid-Induced Hypoxia and Enable Emergent Naloxone Rescue NARRATIVE: We are developing a wearable Opioid Overdose (OOD) Diagnostic device, that will decrease the time from OOD to recognition by bystanders, and therefore decrease time to resuscitation (and possible naloxone administration), with a goal to reduce the fatality rate of OOD in the ambulatory setting. A discreet biosensor device that detects life-threatening OOD with on-device logic and alarms locally, without wireless connectivity needed, is a fundamental improvement in patient safety because it removes all risk of connectivity (e.g. wearable device to mobile-device of User, and then to cloud for data analysis and response, introduces many opportunities for error), and enables patients to be rescued in a variety of circumstances where wireless connection may not be present to transmit the acute event (basement, car, etc). The addition of an adjunct (not required for device function) wireless alert, to people who have been specifically selected by the device User, adds an additional opportunity for intervention in OOD, giving agency to loved ones to act in case of an emergency (they may be nearby, or can call 911) - expanding the opportunities for intervention improves the likelihood of preventing fatal OOD.

Project Terms:
Algorithms; Body Weight; Cardiopulmonary Resuscitation; cardiac resuscitation; heart resuscitation; Charge; Clinical Research; Clinical Study; Communities; Data Analyses; Data Analysis; data interpretation; Emergency Situation; Emergencies; Engineering; Environment; Environmental Monitoring; Ecologic Monitoring; Ecological Monitoring; environmental testing; Exanthema; Exanthem; Rash; Skin Rash; Feasibility Studies; Formularies; Gases; Goals; Gold; Hearing; Recording of previous events; History; Human; Modern Man; Learning; Light; Photoradiation; Logic; Longevity; Length of Life; life span; lifespan; Low Income Population; Marketing; Medicaid; Physiologic Monitoring; Physiological Monitoring; Motion; Naloxone; Persons; Parachuting; Patients; pilot study; Pilot Projects; pressure; Probability; Study Type; study design; Research Design; Investigators; Researchers; Research Personnel; respiratory mechanism; Respiration; Resuscitation; Risk; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Sleep; sun light; Sunlight; Target Populations; Phone; Telephone; Testing; Time; Tourniquets; United States Substance Abuse and Mental Health Services Administration; SAMHSA; Substance Abuse and Mental Health Services Administration; United States Food and Drug Administration; Food and Drug Administration; USFDA; Vision; Sight; visual function; Voice; Measures; Device Designs; Device Safety; Mediating; Neighborhood Health Center; Community Health Centers; Satellite Centers; chronic pain; Blood gas; base; Label; sensor; improved; Acute; Chronic; Clinical; Phase; Physiological; Physiologic; Medical; Evaluation; Distress; Ingestion; Intuition; Hypoxic; Oxygen Deficiency; Hypoxia; Opiates; Opioid; root; Plant Roots; remifentanil; Collaborations; Intravenous; Life; Pulse; Physiologic pulse; Investigation; Hour; Event; Protocol; Protocols documentation; Upper arm; System; Location; Diagnostic Device; Diagnostic Equipment; impression; Performance; stressor; success; biological sensor; Biosensor; Speed; novel; Devices; Reporting; response; Adverse effects; Intervention Strategies; interventional strategy; Intervention; Drops; patient safety; Effectiveness; preventing; prevent; Fatality rate; Data; device development; instrument development; Device or Instrument Development; NIDA; National Institute on Drug Abuse; National Institute of Drug Abuse; Resolution; Enrollment; enroll; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Development; developmental; Output; Instruction; design; designing; Population; handheld mobile device; mobile device; commercialization; loved ones; standard of care; arm; mobile application; mobile app; mobile device application; cloud based; 911 call; Medical emergency; Innovation Corps; I-Corps; opioid use disorder; opiate use disorder; opioid use; opiate consumption; opiate drug use; opiate intake; opiate use; opioid consumption; opioid drug use; opioid intake; communication device; clinical diagnostics; medical diagnostic; opioid overdose; opiate overdose; opiate related overdose; opioid drug overdose; opioid induced overdose; opioid intoxication; opioid medication overdose; opioid poisoning; opioid related overdose; opioid toxicity; Bluetooth; wearable device; wearable electronics; wearable technology; opioid user; Opiate user; Opioid drug user; PWUO; people who use opioids; persons who use opioids; side effect; Home; wireless