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Minimally or Non-invasive Systemic Oxygen Delivery and Carbon Dioxide Removal

Description:

OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): COMBAT CASUALTY CARE OBJECTIVE: Develop a drug, biologic, or device that is capable of facilitating transport of oxygen (O2) into the body and carbon dioxide (CO2) out of the body in a minimally-invasive or non-invasive manner without the need for oxygen generating systems. The proposed product must be usable in an austere environment with minimal clinical staff operation requirements. The ideal product will be usable by medical first responders such as combat medics (or equivalent). The final product will be low size, low weight, low power, stable at temperature extremes, with a prolonged shelf life. DESCRIPTION: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition characterized by failure of O2 and CO2 movement (gas exchange) across the alveolar-capillary membrane. ARDS secondary to trauma or severe illness such as viral and/or bacterial infection or due to direct lung injury such as chemical or smoke inhalation is a major contributor to mortality among critical care patients, resulting in death in 30-50% of those with the condition1. Among survivors, ARDS carries a high degree of morbidity and frequently leads to long-lasting health complications. The respiratory complications of traumatic injury, direct exposure to chemical and/or biological warfare agents, or pandemic respiratory viral illnesses pose a serious threat to operational success, particularly in resource-limited settings. A lack of definitive treatment for ARDS threatens the health of military Service Members and civilians alike.2 Pharmacotherapeutics aimed at treating ARDS have shown promise in preclinical studies but fail to demonstrate success in clinical trials likely owing to the inability of drugs to reach the damaged alveolar surface either directly or systemically. Clinical management of ARDS is supportive and involves the use of adjunctive measures to correct critical hypoxemia such as mechanical ventilation for respiratory failure, systemic corticosteroids to reduce inflammation and, if available, extracorporeal life support (ECLS) to deliver O2 and remove CO2 directly from the blood. Despite the availability of these adjuncts, mechanical ventilation may result in cellular-level trauma as the alveoli are stretched and deformed under positive pressure, thus contributing to additional lung damage; corticosteroids reduce inflammation but the underlying inflammatory processes leading to ARDS remain; and ECLS is not available in most hospitals, and when available carries a high complication rate and requires much logistical support and manpower at a time when healthcare providers are already stretched thin. Consequently, there is a strong need for new or refined treatment options for ARDS-associated refractory hypoxemia and hypercapnia, particularly at the point when the lungs are no longer able to effectively facilitate normal O2 and CO2 transport. The Department of Defense operates worldwide, including in remote and austere environments without access to modern medical facilities. The task of caring for traumatically injured and/or critically ill soldiers on the battlefield, especially in isolated regions, remains a challenge and warrants the need to develop effective treatment capabilities for ARDS. This topic seeks the identification and development of a minimally-invasive or non-invasive method of O2 delivery and removal of CO2 for ARDS-induced respiratory failure. Ideally, the candidate product will utilize unique treatment approaches, for example, nanotherapeutics capable of facilitating gas transport through fluid-filled, inflamed alveoli or intravenous O2 delivery coupled with miniaturized extracorporeal CO2 removal/scavenging. An ideal product will operate without the need for O2 generating systems, although proposals presenting a simplified means of generating O2 for use with a unique product will be considered. The successful candidate product could be incorporated 1) into an existing device, 2) into an inhalable formulation, or 3) into a systemic delivery system. The proposed product and delivery system (if applicable) is expected to have no, or minimal, toxicity and should be easily administered by a minimal number of health care personnel in resource limited settings. PHASE I: This Phase will demonstrate the feasibility of producing a candidate drug, biologic, or device, and will demonstrate criteria required for success. During this phase the researcher will define and characterize a candidate drug, biologic, or device that is capable of directly or indirectly delivering systemic O2 and removal of CO2 as stated in the Objective and Description. Proposals should describe the rationale for the appropriateness of the proposed product. Other supportive data may also be provided during this 6-month Phase I, $250,000.00 (max) effort. Proposals should contain preliminary data (published or unpublished) supporting the rationale for the development of candidate product(s) and data related to the mechanism of action of the proposed drug(s)/biologic(s) (if applicable), if known. Describe how the product will be usable in a resource-limited setting. The Phase I effort will include prototype plans to be developed under Phase II. Provide a plan for practical deployment of the proposed O2 delivery/CO2 removal product. Animal/human testing is discouraged during the Phase I (6 month) period. Deliverables of this phase include: 1) strong proof-of-concept and rationale for further development of the candidate product, 2) a prototype candidate drug, biologic, device, or system, and 3) a detailed Phase I final report that includes concepts and plans to develop and test the prototype product, including future FDA regulatory considerations. PHASE II: The investigator shall design, develop, test, and validate the prototype developed during Phase I. The testing and practical implementation of the prototype product should be relevant to ARDS-associated respiratory failure. During this 2-year, $3M (max) effort the performer may consider early communication with the FDA for guidance and to ensure that regulatory clearance can be pursued during Phase III. Required Phase II deliverables will include: 1) Successful refinement of a working prototype, 2) further evaluation of the efficacy of the product(s) in a relevant in vivo model(s) of ARDS-associated respiratory failure (pre-clinical studies), 3) detailed annual and final reports about the overall project including all data that demonstrate the ability to address the problem as stated in the Objective and Description and 4) regulatory strategy with a clear FDA clearance plan. RESEARCH INVOLVING ANIMAL OR HUMAN SUBJECTS: All research involving animals and humans (to include use of human biological specimens and human data) shall comply with the applicable federal and state laws and agency policy/guidelines for protection of animals and/or humans used for research purposes. Research involving the use of animals or humans may not begin until the U.S. Army Medical Research and Development Command's Office of Human Research Oversight (OHRO) approves the protocol. Written approval to begin research or subcontract for the use of human subjects under the applicable protocol proposed for an award will be issued from the U.S. Army Medical Research and Development Command, OHRO, under separate letter to the Contractor. Non-compliance with any provision may result in withholding of funds and or the termination of the award. PHASE III DUAL USE APPLICATIONS: If successful, Phase II work will result in a product that directly or indirectly treats hypoxemia and hypercapnia and is commercially applicable to both civilian and military applications. Civilian and/or military healthcare professionals could utilize the newly developed product to treat respiratory failure in medical facilities worldwide, reducing morbidity, mortality and global healthcare costs. The product would be particularly useful during global pandemics that threaten to overwhelm emergency departments with respiratory failure patients. The developed product may transition to an Acquisition Program managed by the Service Product Developers for inclusion into the fielded medical system, or be available to Service Medical Treatment Facilities, for the treatment of those who suffer from hypoxemia and/or hypercapnia resulting from respiratory failure after combat- and noncombat-related trauma or critical illness. During Phase III, further assessment of effective dose ranges (if applicable) and/or application frequencies (if applicable) may be conducted. In addition, applicants are expected to conduct a pre-IND (drugs/biologics) or pre-submission (devices) meeting with the FDA prior to the completion of Phase III. A plan for protection of intellectual property should be created and executed. The small business should have plans to secure funding from non-SBIR government sources and/or the private sector to develop or transition the prototypes into a viable product for sale to the military and/or commercial markets. The end-state of the research will be the full development of one or more innovative products that minimally- or non-invasively corrects hypoxemia and hypercapnia and that can be administered to or used on military and civilian patients in a clinically relevant manner. REFERENCES: 1. Bellani G., Laffey J.G., Pham T., Fan E., Brochard L., Esteban A., Gattinoni L., Van Haren F.M.P., Larsson A., McAuley D.F., Ranieri M., Rubenfeld G., Thompson B.T., Wrigge H., Slutsky A.S., Pesenti A. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA - J. Am. Med. Assoc. 2016;315:788–800. doi: 10.1001/jama.2016.0291; 2. Matthay M.A., Ware L.B., Zimmerman G.A. The acute respiratory distress syndrome. J. Clin. Invest. 2012;122:2731–2740. doi: 10.1172/JCI60331. KEYWORDS: respiratory failure, ARDS, ALI, hypoxia, hypoxemia, hypercapnia, ECMO, oxygenation, CO2, O2, ventilation, scavenging, mechanical ventilation, respiratory, pulmonary, lung, artificial respiration
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