TOPIC RELEASE 1_REV 2.pdf

THE PHASE I PROPOSAL SUBMISSION DEADLINE FOR THE FOLLOWING

TOPICS IS MARCH 20, 2020 AT 2:00PM EASTERN DAYLIGHT TIME (EDT).

THE DEADLINE TO SUBMIT QUESTIONS RELATED TO THE FOLLOWING

TOPICS IS FEBRUARY 17, 2020.

Topic CBA-01 Diagnostic Biomarkers for Predicting Severity of Disease

Background:

Timely medical evacuation of casualties has been credited with dramatically reducing morbidity and mortality in recent US military operations (1, 2). Unrestricted transport of injured or sick Service members and effective triage is projected to play a critical role during mass casualty events, including attacks with biological or chemical agents. Medical transport also typically presents the first opportunity for performing physiological monitoring and simple/quick diagnostic tests and the evacuee’s condition is often assessed to inform a triage/risk assessment decision. This topic seeks to develop an assay that informs this critical decision. In recent military operations, medical transport in the battlefield have been requested for a variety of conditions. These range from acute stress, trauma and multi organ injury from accidents/explosives/gun shots, neurological disorders, acoustic injury, spinal contusion, cardiovascular diseases, digestive tract diseases, and sepsis to fever of unknown origin (3, 4).

This topic seeks new and novel diagnostic assays that can be administered before or during medical transport to provide a risk score indicative of severe clinical outcomes and associated need for hospital based intensive care. The diagnostic score can inform patient transport and triage decisions, improving resource allocation and clinical outcomes, especially during mass casualty events. Risk associated with exposure to Chemical or Biological Agents must be incorporated into the overall risk score, though identification of any causative agent is not a requirement of this topic. Overall, the assay and accompanying analysis will provide a numerical value that may be used to support complex decisions involving prioritization of care.

A review of current literature suggests that the development of an assay for predicting disease severity is increasingly becoming feasible. Biomarkers are being identified and validated to predict severe outcomes from several acute conditions. For example, hematocrit appears to be correlated with loss of blood due to hemorrhage or injury; Troponin, B-type natriuretic peptide (BNP) and N-terminal proBNP levels appear to be correlated with cardiovascular disease and heart failure; Procalcitonin (PCT) levels appear to be correlated with bacterial sepsis (5, 6). In addition, certain markers such as Presepsin, TRAIL, and sTREM-1 are reported to be correlated with severe outcomes in hospitalized patients (7, 8). A number of clinical algorithms that combine physiological and laboratory inputs to predict clinical outcomes have also been implemented in healthcare settings worldwide with varying degrees of success. This topic hopes to mature the field of diagnostic biomarkers for predicting severity and advance this capability for use in operational settings for the warfighter.

Objective:

This topic seeks new and novel diagnostic assays that can be administered before or during medical transport to provide a risk score indicative of severe clinical outcomes and associated need for hospital based intensive care. Successful efforts will:

1. Identify biomarkers that correlate with severe clinical outcomes from existing and/or proposed studies

2. Identify biomarkers that predict severe outcomes from most types of acute conditions that are likely to require medical transport in military operations (e.g. acute stress, hemorrhage, high fever, sepsis, myocardial infarction, etc.) with specific emphasis on biomarkers correlated with exposure to chemical or biological agents. Biomarkers for the clinical course of chronic conditions (e.g. cancers, dementia) are not a focus of this effort.

3. Design assays that measure the identified biomarkers. These may be protein, nucleic acid, and/or other markers as required.

4. Use clinical samples that can be collected relatively easily during medical transport (e.g.

whole blood or sputum). Samples that are harder to collect in the envisioned operational setting (e.g. Cerebrospinal fluid, stool) or involving additional sample preparation (e.g.

preparing serum from whole blood) are less desirable.

5. Develop an algorithm that takes biomarker assay results and other available information as appropriate to produce a risk score that predicts severity of disease. This score needs to be correlated with observable clinical outcomes including mortality, length of hospital stay, or other measures indicative of severe disease.

6. The algorithm may also identify the likely clinical cause or outcome. As the biomarkers and signatures for different conditions (e.g. TBI, cardiovascular disease, or chemical or biological exposure) are likely to be distinct, the algorithm may identify the suspected condition and associated severe clinical outcomes.

7. Leverage available routine physiological data such as respiratory rate, blood oxygen levels, temperature or heart rate information that can be collected in an ambulance or medical transport, if necessary/appropriate for calculating the risk score.

8. Develop the study design leveraging biostatistics expertise to ensure reasonable confidence in the identified biomarkers and risk score algorithm.

9. Leverage existing technologies for measuring biomarkers (e.g. RT-PCR, ELISA, microarrays, sequencing) as appropriate. Developing novel chemistries or diagnostics technologies is not a focus of this effort. Integrated sample preparation, miniaturization, ruggedization, or other activities to adapt the assay to a field expedient format are also not an emphasis of this effort at this time—but may become the focus for follow-on work or written in as optional tasks in the statement of work.

10. Deliver the requested assays, algorithm, and validation data within 3 years of award.

Also, the proposal needs to be broken down into clear milestones that may be used to make go/no-go decisions for continued funding.

11. Focus on demonstrating, identifying and validating an assay and risk score algorithm that demonstrably correlates with severe clinical outcomes.

Offerors are encouraged to develop R&D collaborations with other organizations in Government, academia, and the private sector to broaden and strengthen their knowledge, experience and capabilities. Additionally, offerors are encouraged to take advantage of specialized resources in the DoD and other Government agencies such as facilities/capabilities.

Impact:

This topic will advance the science to ultimately support the warfighter with a diagnostic test that can be used before, during, or following MEDEVAC/CASEVAC and inform transportation and triage decisions. Such a diagnostic capability can be critically important in prioritizing care, especially in situations requiring difficult medical decisions to be made—following a mass casualty event (including attack with a chemical or biological agent), or in conflicts where heavy casualties are projected and patient transport options are restricted. The envisioned diagnostic test will help direct the injured or sick soldier to appropriate medical care and alert physicians to their general risk profile. These individual benefits are likely to add up to a broader impact on improved force recovery and readiness.

References:

1. Fazal, TM, Ramussen, T, Nelson, Paul, Carlton, PK. How long can the US Military’s Golden Hour Last? War on the Rocks. October 8, 2018.

https://warontherocks.com/2018/10/how-long-can-the-u-s-militarys-golden-hour-last/

2. Keenan, S, Riesberg, JC. Prolonged Field Care: Beyond the Golden Hour. Wilderness and Environmental Medicine, 28(2), pp S135-S139.

https://doi.org/10.1016/j.wem.2017.02.001

3. Korzeniewski K, Pieniuta S. Reasons for medical evacuation of soldiers serving in Iraqi Freedom Operation. Int Marit Health. 2011;62(1):77-81.

4. Leading causes of medical evacuations out of war zones: It’s not combat injury. Johns Hopkins Medicine News.

https://www.hopkinsmedicine.org/news/media/releases/leading_cause_of_medical_evacu ation_out_of_war_zones_its_not_combat_injury

5. Ohigashi H, Haraguchi G, Yoshikawa S, Sasaki T, Kimura S, Inagaki H, Hachiya H, Hirao K, Isobe M. Comparison of biomarkers for predicting disease severity and long-term respiratory prognosis in patients with acute pulmonary embolism. Int Heart J.

2010;51(6):416-20.

6. Dolin HH, Papadimos TJ, Stepkowski S, Chen X, Pan ZK. A Novel Combination of Biomarkers to Herald the Onset of Sepsis Prior to the Manifestation of Symptoms.

Shock. 2018 Apr;49(4):364-370. doi: 10.1097/SHK.0000000000001010. Review.

7. Richard-Greenblatt M, Boillat-Blanco N, Zhong K, Mbarack Z, Samaka J, Mlaganile T, Kazimoto T, D'Acremont V, Kain KC. Prognostic accuracy of sTREM-1-based algorithms in febrile adults presenting to Tanzanian outpatient clinics. Clin Infect Dis.

2019 May 18. pii: ciz419. doi: 10.1093/cid/ciz419.

8. Schenck EJ, Ma KC, Price DR, Nicholson T, Oromendia C, Gentzler ER, Sanchez E, Baron RM, Fredenburgh LE, Huh JW, Siempos II, Choi AM. Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsis. JCI Insight.

2019 May 2;4(9). pii: 127143. doi: 10.1172/jci.insight.127143. eCollection 2019 May 2.

https://warontherocks.com/2018/10/how-long-can-the-u-s-militarys-golden-hour-last/ https://doi.org/10.1016/j.wem.2017.02.001 https://www.hopkinsmedicine.org/news/media/releases/leading_cause_of_medical_evacuation_out_of_war_zones_its_not_combat_injury https://www.hopkinsmedicine.org/news/media/releases/leading_cause_of_medical_evacuation_out_of_war_zones_its_not_combat_injury

Topic CBS-01 Innovative Approaches for Improving Drug Delivery to the Central Nervous System

Background:

Chemical warfare agents (CWA) are among the most deadly weapons of mass destruction (WMD) known. Significant classes of CWA include organophosphate nerve agents (OPNA) such as soman, VX, sarin and Fourth Generation Agents, such as Novichok. OPNA act by inhibition of acetylcholinesterase (AChE) resulting in reduced hydrolysis of the neurotransmitter, acetylcholine. Accumulation of acetylcholine causes overstimulation of the acetylcholine receptor. Physiological responses to OPNA exposure include hypotension, rhinorrhea, wheezing and diarrhea. Significant exposure to OPNA may be fatal. As a result, OPNA poses a significant threat to military forces.

Current antidotes include charged oximes that are capable of reactivating AChE after its inactivation by OPNA. Although pralidoxime; 2-pyridine aldoxime methyl chloride [2-PAM]), the FDA-approved oxime, reactivates AChE in the periphery, it does not efficiently cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), which is an important site of OPNA toxicity. Further limiting its utility, the spectrum of 2-PAM is relatively narrow and is not effective against the full range of OPNA.

OPNA can reach and have longer-term effects on the CNS. Current countermeasures do not efficiently cross the BBB. This shortcoming creates a significant treatment gap. As a result, improving CNS delivery of current nerve agent therapeutics with proven in vivo efficacy would be useful in treating OPNA-exposed individuals. It is hypothesized that such a therapeutic could increase survival, and potentially ameliorate the acute and longer-term effects of OPNA on CNS function.

Objective:

Proposals are sought for drug delivery technologies that improve the BBB permeability of 2- PAM in order to treat OPNA exposure within the CNS. Technologies in all stages of drug development will be considered, from drug discovery and novel approaches through Phase I clinical trials. Later stage delivery technologies/platforms will have priority over novel approaches not yet tested in the clinic.

Areas of research that will not receive consideration under this topic include proteins or enzymatic bioscavengers designed to remove nerve agent from circulation, acetylcholine receptor inhibitors, AChE inhibitors, new anticonvulsants, gamma-aminobutyric acid or glutamate receptor modulators, and/or the use of reactivators other than 2-PAM.

Strategies may target active or passive transport mechanisms and may include, but are not limited to, the following:

• Nanoencapsulation1, such as:

o Dendrimers o Liposomes o Carbon nanotubes o Polymeric micelles

• Pharmaco-chemical strategies (i.e., making a drug more lipophilic) such as:

o Genetic engineering o Drug conjugates

Delivery technologies that focus on delivering 2-PAM to the CNS are preferred. Research programs spanning the drug development process up to Phase 1 clinical trials (TRL6) may be appropriate. Regardless of program maturity, offerors should propose milestone driven projects.

R&D collaborations with other organizations within the Government, academia, and the private sector are acceptable.

The following attributes should be considered to develop the most attractive proposal:

1) Medical Countermeasure (MCM) candidates which demonstrate compatibility with military operations, such as ease of administration, storage stability, and minimal number of administrations to provide desired protection;

2) Potential side effects of MCM;

3) MCM with broad spectrum application across a wide spectrum of OPNA;

4) MCM that are able to penetrate the BBB;

5) Minimal cost per dose;

6) MCM allowing for repeat administration with limited immunogenicity;

7) Fully developed comprehensive TPP and regulatory strategy, appropriate to program maturity;

8) Preliminary data supportive of proof-of-concept.

Impact:

The results of the proposed research efforts will ultimately provide the Chemical and Biological Defense Program with novel MCM technology for the treatment of the adverse effects associated with a range of OPNA in the CNS. This product will allow for acute care on the battlefield and will prevent neurodegeneration, promoting an enhanced quality of life for OPNA-afflicted Warfighters.

References:

1. Kumari, A., Singla, R., Guliani, A., & Yadav, S. K. (2014). Nanoencapsulation for drug delivery. EXCLI journal, 13, 265–286.

Topic CBS-02 Reaerosolization/Resuspension Processes of Disseminated Aerosol Particles

Background:

A chemical or biological agent threat may be released in an aerosol form. The released aerosol particles may be of different sizes, masses, etc. and will eventually settle out and deposit on various surfaces. Unfortunately, these aerosol particles may still be hazardous and a potential threat to personnel – especially if they again become airborne. While we may understand the degradation and fate of biological and chemical particles on various surfaces in particular environments, the mechanisms for displacement of those particles from the various surfaces are not well defined and the displacement variables are not well characterized.

Many factors influence reaerosolizing or resuspending these particles. For example, the deposition surfaces may be rough or smooth, thus affecting the strength of the particles adhesion.

Similarly, the characteristics and properties of the particle itself are factors; size, morphology, chemical composition and other adhesive or adsorptive properties affect the ability of the particle to be removed from the surfaces. Hence, surface-surface interactions (i.e., particle-substrate chemical and physical interactions) play a large role in the ability of the particle to be released from the surface and again become airborne.

The goal of this topic is to understand how the chemical and physical properties of deposited aerosol particles and their substrates affect their ability to be reaerosolized or resuspended.

Results from the studies will provide insight into the mechanisms and processes behind how deposited aerosol particles (both chemical and biological) can again become aerosolized (thus again posing a potential hazard to personnel), and enable development of defensive capabilities (e.g., predictive models to provide hazard assessment information to decision makers, protective equipment, etc.) needed to protect personnel from the resulting threats and hazards.

Objectives:

Receive proposals that, to the extent practicable, identify dependencies and variables associated with aerosol particle reaerosolization and resuspension, and describing the reaerosolization and resuspension mechanisms in a manner that is as composition- and surface-agnostic as possible.

1. Determine the chemistry and physics affecting the ability of an aerosol particle to be reaerosolized or resuspended, to include the chemical and physical properties of the substrate from which the particle originates. Factors to consider include, but are not limited to, those inherent to surface-surface interactions:

a. Particle size, mass, density, morphology, etc.

b. Substrate roughness

c. Adhesive and adsorptive forces between the particle and substrate

d. Shear stress parameters needed to remove the particle from the substrate surface with respect to these factors, including those related to mechanisms beyond wind velocity and angles (e.g., reaerosolization due to walking or other similar disturbance)

e. Composition of the particle (e.g., wet vs. dry aerosols, multi-component particles as found in biological aerosols, etc.) with respect to the substrate.

2. Assess and evaluate the reaerosolization or resuspension properties for a specific chemical or biological aerosol particle, focusing on the effects of the chemical characteristics inherent to the particle composition and with respect to the above variables and dependencies.

Only proposals addressing these specific objectives, or combinations of objectives, will be considered. Specific biological organisms proposed for use in the studies should be identified, and particle composition(s) described in as much detail as practicable. For biological aerosols, only bacterial, viral and biologically-produced toxin aerosols will be considered (i.e., no fungal, pollen, etc.).

Again, to the extent practicable, show how the determined dependencies and variables influence reaerosolization and resuspension mechanisms in a way that is as composition- and surface-agnostic as possible.

Impact:

1. Information generated from these studies will be used to develop or improve upon hazard and risk assessment models, providing more precise and accurate predictive tools for decision making and other defensive purposes.

2. Results will enable the determination and/or understanding of reaerosolization mechanisms, providing insight into protective and defensive capability development.

References:

1. Kesevan, J. et al. “Experimental and Computational Study of Reaerosolization of 1 to 5 µm PSL Microspheres Using Jet Impingement.” Aerosol Science and Technology (2017) 51:3, 377-387.

2. Fillingham, P. et al. “Characterization of Adhesion Force in Aerodynamic Particle Resuspension.” Journal of Aerosol Science (2019) 128, 89-98.

3. Kottapalli, K.; Novosselov, I. V. “Experimental Study of Aerodynamic Resuspension of RDX Residue.” Aerosol Science and Technology (2017) 53:5, 549-561.

Topic CBS-03 Developing Hemostatic Wound Dressings to Treat the Adverse Effects of CWA Exposure in Wounds

Background:

Chemical warfare agents (CWAs) are among the most deadly weapons of mass destruction (WMD) known. The most significant classes of CWA include nerve agents such as VX and sarin, vesicants including sulfur mustard, and pharmaceutical-based agents such as fentanyl.

The management of casualties with exposures to chemical warfare agents (CWAs) is well documented since the first battlefield use of chemical weapons in World War I (WWI). Medical management has evolved from supportive care only to the development of specific therapeutic countermeasures. This approach has been successful in providing targeted solutions in both the prevention and the treatment of insult or injury from many CWAs. These medical chemical countermeasures include the Antidote Treatment Nerve Agent Autoinjector (ATNAA) used to treat personnel exposed to the agent, and Reactive Skin Decontamination Lotion (RSDL), a lotion designed for spot decontamination to remove and neutralize CWAs on the skin.

In the case of conventional traumatic casualties, wounds are treated with gauze and other wound packing and dressings that are often infused with a hemostatic agent, designed to promote coagulation. QuikClot Combat Gauze is a wound dressing used in combat casualty care.

However, battlefields may be contested with the use of chemical and biological agents along with conventional tactics. Thus, combat casualties may experience combined traumatic injuries and chemical contamination.

To counter the threat of chemical combined injuries, there is a need for the development of wound care technologies that can both optimally manage complex traumatic injury and neutralize chemical warfare agents. A multi-use countermeasure will offer the life-saving and prolonged care required in a complex battlefield environment containing multiple threats.

Objective:

DTRA seeks proposals for a multifunctional wound care and chemical warfare agent decontamination product that can be applied to wounds that may have occurred in a chemical agent environment. The dressing should be able to neutralize or remove chemical agents, protect the wound, and support wound healing. The product should be for use on both superficial and more traumatic, complex wounds. Proposals that include wound dressings with hemostatic agents, to promote rapid blood coagulation, or other wound-healing characteristics, and those that support prolonged field care, where evacuation to higher level care may be delayed up to 72 hours, will be prioritized. Therapeutic products incorporated into a wound dressing are likely to be delivered systemically. This suggests that such a wound dressing could be used as a means of administering appropriate systemic drugs; proposals which consider this possibility are of interest.

Proposals considering products in preclinical development must demonstrate a clear path towards clinical phase I studies with Investigational New Drug (IND) regulatory submission.

Ideal candidates will have successfully completed preliminary in vitro data and/or have demonstrated safety and efficacy profile in an animal model, and proposals should address the following key elements:

1) Development of a Target Product Profile (TPP) and regulatory strategy for IND submission and progression to phase I clinical trials

2) Provide proof-of-concept data to demonstrate efficacy and/or manufacturability of the product and feasibility to scale up

3) Studies using live agents (including nerve agents, vesicants, and pharmaceutical-based agents) rather than only pesticides and simulants

Offerors are encouraged to develop R&D collaborations with other organizations in Government, academia, and the private sector to broaden and strengthen their knowledge, experience and capabilities. Additionally, offerors are encouraged to take advantage of specialized resources in DoD and other Government agencies such as facilities/capabilities for chemical surety certification, non-GLP preclinical studies, ADME (Absorption, Distribution, Metabolism, and Excretion) testing and manufacturing. If applicable, it is encouraged that engagement with the FDA be pursued throughout the contract.

Types of proposals that are outside the scope of this topic include those with simple alternatives to RSDL for decontamination of intact skin only; those that fail to address decontamination of CWA from open wounds; and those that can treat abrasions only but not serious traumatic wounds. Such proposals will not be evaluated further.

Impact:

The results of proposed research efforts will ultimately provide the Warfighter with protection against chemical warfare agents that can be utilized in wounds and may promote wound healing.

This combination product will allow for extended care on the battlefield and will promote healing, to ensure Warfighter return to duty.

References:

1. TPP FDA Guidance:

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan ces/ucm080593.pdf

2. Product Development under the Animal Rule FDA Guidance:

https://www.fda.gov/downloads/drugs/guidances/ucm399217.pdf

3. “Early drug discovery and development guidelines: for academic researchers, collaborators, and start-up companies” Hughes, M. et al. Assay Guidance Manual [Internet], May 1, 2014. PMID: 22553881.

Topic CBS-04 Physical and Chemical Property Changes of Disseminated Biological Aerosol Particles

Background:

A biological agent threat may be released in an aerosol form. The released aerosol particles may be of different sizes, masses, etc., but change over time after release. For example, such particles may gain or lose hydration, and environmental and atmospheric factors may affect particle survivability and viability [Haddrell, 2017; Fernandez, 2019]. Fundamental questions regarding mechanisms of viability and survival of the biological aerosol during aerosol transport still remain [Haddrell, 2017].

The goal of this topic is to understand how the chemical and physical properties of biological aerosols change after being released into the atmosphere, and the underlying mechanisms behind the changes and their effects on the viability of the biological particle itself. Results from the studies will provide insight into how biological aerosols survive and remain hazardous to personnel (through toxicity or infectivity). These data will inform decision makers, and enable development of defensive capabilities needed to protect personnel from the threats and hazards posed by these aerosols.

Objectives:

1. Understand or otherwise determine changes to the physical and chemical properties of disseminated biological aerosol particles, specifically the dynamically-occurring changes resulting after the particle becomes airborne. Property dependencies and variables to address in the studies would include those associated with the fate of the particle during transport, and the viability of the biological component of the particle with respect to its infectious capabilities. Such dependencies and variables may include any or all of the following:

a. Hygroscopicity, viscosity, etc. (and their inherent variables and dependencies)

b. Relative humidity and temperature

c. Dynamic loss of the particle components in the atmosphere (e.g., water, solutes), and/or the breakup of the particle that results in changes to particle composition

d. Mass and size changes with respect to wind speed and distance after dissemination.

2. Assess and evaluate the survivability and viability of a specific bacterial or viral biological aerosol to cause infection with respect to any physical and chemical property changes occurring once the aerosol has been disseminated.

considered. Proposals should demonstrate an understanding of previous research in the area, and how the proposed research advances knowledge and understanding of the fate of disseminated biological aerosols. Specific biological organisms proposed for use in the studies should be identified, and particle composition(s) described in as much detail as practicable. Only bacterial, viral and biologically-produced toxin aerosols will be considered (i.e., no fungal, pollen, etc.).

Impact:

1. Information generated from these studies will be used to develop or improve upon hazard and risk assessment models, providing more precise and accurate predictive tools for decision making and other defensive purposes.

2. Results will enable the determination and/or understanding of bioaerosol infection mechanisms, providing insight into potential countermeasure, diagnostic and other defensive capability development.

References:

1. Haddrell, A. E.; Thomas, R. J. “Aerobiology: Experimental Considerations, Observations and Future Tools.” Applied and Environmental Microbiology (2017) 83(17), e00809-17

2. Fernandez, et al. “Assessing the Airbornes Survival of Bacteria in Populations of Aerosol Droplets with a Novel Technology”. J. R. Soc. Interface (2019) 16, 20180779

Topic CBS-05 Physics of Explosively Disseminated Compacted Powder Agglomeration, Breakup and Physics

Background:

While the transport and diffusion of explosively disseminated powders is increasingly well characterized, the physics underlying the early time period after the explosive initiation (i.e., first hundreds of microseconds) is not. There is a current knowledge gap in the phenomena of early stage explosive dissemination of compacted powders (e.g., CB threats), especially with respect to particle agglomeration and breakup.

The goal of this topic is to understand the fundamental physics underlying the first hundreds of microseconds of the explosive dissemination of compacted powders, especially with respect to particle agglomeration and breakup. This project will provide novel insight into these early stages of explosive dissemination by understanding the underlying physics and elucidating the tendency of compacted powders to agglomerate and break up, enabling development of better and more accurate predictive models and other defensive/protective capabilities.

Objectives:

1. Understand the fundamental physics and chemistry underlying the first hundred microseconds of the explosive dissemination of compacted powders, to include the tendency of compacted powders to agglomerate and break up during the initial phases of the explosive dissemination:

a. Describe the physics mathematically

b. Include variables associated with the compacted powder

i. Initial particle size

ii. Electrostatic properties

iii. Compacting pressure

iv. Relevant chemical and physical properties (e.g., density, melting point, etc.).

2. Understand the explosive effects on the compacted powder, including the agglomeration and breakup tendency, during the initial phases of the explosive dissemination. Factors to consider include but are not limited to:

a. Thermal effects

b. Shock wave

c. Pressures.

considered. Experimental approaches are desired, though theoretical approaches will also be considered.

Impact:

1. Understanding the early stage dissemination can be extrapolated for use with larger-scale dissemination studies

2. Results will be used in data interpretation of ongoing laboratory aerosol studies, and for use in model development

3. Early phase understanding of particle behavior will improve accuracy of longer term prediction of behavior

References:

1. Milne, et al. “Dynamic fragmentation of powders in spherical geometry”. Shock Waves

(2014) 24:501–513 Milne, et al. “Dynamic fragmentation of blast

Topic CBS-06 Medical Countermeasures to Prevent or Treat the Adverse Effects of Opioid Intoxication

Background:

Opioids are widely used for a variety of therapeutic applications in the relief of moderate to severe pain. However, a myriad of synthetic analogs of naturally occurring opioids have been developed, many of which are derivatives of fentanyl and are generally more potent than the parent compound.

Opioids efficiently cross the blood brain barrier, and are capable of causing acute intoxication.

Both natural and synthetic opioids act predominantly via the µ-opioid receptor, a G-protein-coupled receptor expressed in a variety of tissues. In the central nervous system, these effects reduce sensitivity to pain, resulting in analgesic effects, however, a negative side effect of opioid use is opioid-induced respiratory depression (OIRD). The current pharmacopeia contains several µ-opioid receptor antagonists (e.g., naloxone, naltrexone, and nalmefene) which prevent opioid action through competitive binding of receptor sites. While µ-opioid receptor antagonists are able to block deleterious effects of opioid intoxication, they also introduce additional and unwanted side effects which are disadvantageous, especially in the prevention of opioid use for pain management. An ideal opioid medical countermeasure would protect against potent synthetic opioids while simultaneously preserving the ability to utilize select opioids for pain management while also blocking the intoxication and respiratory depression effects.

Objective:

Proposals are sought for novel and innovative therapeutic Medical Countermeasures (MCMs) to protect against the adverse effects of synthetic fentanyl based opioids. MCMs in all stages of drug development will be considered, from drug discovery through Phase I clinical trials. Areas of research that consider repurposing and reformulation of FDA approved, late-development, or failed candidates for other indications are of interest as well. Novel MCMs considered can include small molecules, biologics, and nanotechnologies, among others.

Areas of research that will not receive consideration under this topic include previously developed FDA approved antagonist MCMs (e.g., naloxone, naltrexone, nalmefene).

Areas of interest for research include the following:

1. Development of non-antagonist opioid MCMs and other novel opioid MCM technologies that protect against potent opioids while allowing for the use of select opioids in pain management.

2. Development of novel compounds which reduce OIRD and/or promote respiratory recovery as treatment to opioid exposure.

MCMs that can address areas of interest 1 and 2 are highly desirable. Research plans can span the drug development timeline up to Phase I clinical trials (TRL6), however, offerors should propose milestone driven projects. R&D collaborations with other organization within the Government, academia, and the private sector is acceptable.

The following attributes should be considered in order to be successful:

1. MCM candidates which demonstrate compatibility with military operations, such as ease of administration, storage stability, and minimal number of administrations to provide desired protection.

2. Potential side effects of MCMs.

3. MCMs with broad spectrum application across a wide spectrum of opioids

4. Economical cost per dose to allow for full force protection.

5. MCM allowing for repeat administration with minimal immunogenicity.

6. TPP and regulatory strategy.

7. Preliminary data to support proof-of-concept will be considered favorably.

The results of the proposed research efforts will ultimately provide the Chemical and Biological Defense Program with novel MCMs for the treatment of the adverse effects of synthetic opioid based compounds.

References:

1. Albert Dahan, M.D., Ph.D.; Leon Aarts, M.D., Ph.D.; Terry W. Smith, Ph.D. (2010), Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression;

Anesthesiology, 112, 226-238, doi: https://doi.org/10.1097/ALN.0b013e3181c38c25

2. HHS PHEMCE TRLs:

https://www.medicalcountermeasures.gov/trl/integrated-trls/ https://www.tandfonline.com/doi/full/10.1080/20961790.2018.1460063 https://doi.org/10.1097/ALN.0b013e3181c38c25 https://www.medicalcountermeasures.gov/trl/integrated-trls/

Topic CBT-01 Closed-Circuit Combined Unit Respirator System

Background:

The Joint Program Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO- CBRND) and Defense Threat Reduction Agency Protection & Hazard Mitigation Division (DTRA RD-CBT) are seeking development of innovative solutions to incorporate powered air purifying respirator (PAPR) technologies into closed-circuit, self-contained breathing apparatus (CC-SCBA) systems while reducing the size, weight, power, and logistical requirements compared to existing CC-SCBA technologies. CC-SCBAs and PAPRs are utilized by a variety of military, first response, industrial, pharmaceutical, and other applications for respiratory protection when highest levels of contamination are present, suspected, and/or the environments encountered may be oxygen deficient.

Current CC-SCBA technologies are used in a variety of mission sets, but often bring a heavy thermal and physiological burden due to the effects of wearing heavy protective equipment while encapsulated within high level protection garments. In addition, nearly all man-mounted applications of CC-SCBA remove carbon dioxide from the closed breathing loop through use of sorbent materials that, while efficient, use chemistry that is highly exothermic and promotes human exhaustion.

Additionally, the user’s reporting unit faces a substantial logistical burden to support use of SCBA equipment due to the need for cooling ice in the breathing loop and on-hand supply of system consumables, such as carbon dioxide sorbents and oxygen cylinders, required for multiple systems required during one mission. Because the closed loop system for breathing necessitates use of the consumable sorbent immediately upon mask donning, critical system consumables are used while the subject is donning additional protective equipment, conducting all pre-mission checks, traversing areas from the command post to the target area, and returning from the “hot zone” to the decontamination line. These activities limit total mission duration based on oxygen supply and carbon dioxide scrubbing capability. Incorporation of a PAPR mode into the respirator system would preserve CC-SCBA capacity until activation just prior to entry into the “hot zone” or target area. Use of a PAPR mode during dress out and mission traversing would also reduce the thermal and physiological burden during mission performance.

Objective:

This topic seeks innovative solutions to incorporate PAPR technologies into CC-SCBA systems while reducing the size, weight, and power (SWaP), and logistical requirements, compared to existing CC-SCBA technologies.

This system will be utilized with currently-issued military respirators and breathing hoses. As such, the project will focus on prototyping a system that provides the PAPR and SCBA capabilities, with the respirator and breathing hoses required to complete the system treated as auxiliary components. The Government seeks to leverage existing and emerging technologies to provide a next generation solution that provides a quantifiable increase in capability and decrease in logistical burden, compared to other existing fielded CC-SCBA technology.

Successful efforts will develop a prototype, combined unit respirator system that provides the following minimum capabilities:

1. Two modes of respirator protection: 1) Powered air purifying (respirator system containing an overpressure), and 2) closed-circuit self-contained breathing loop (a respirator that utilizes a closed breathing loop providing supplemental oxygen and removal of carbon dioxide).

2. Seamless transition between protection modes to meet operational needs with no loss of protection during transition and ability to perform multiple transitions between modes.

3. System must maintain average oxygen (O2) concentration of not less than 19.5% while operating in SCBA mode.

4. System cannot exceed maximum average carbon dioxide (CO2) levels in breathing loop of 1.0% throughout operation in SCBA mode.

5. System provides permeation and penetration resistance in accordance with section (1) of reference 1.

6. Weight of less than 27 pounds (including batteries) with harnessing such that the system can be worn and secured onto the back of the user.

7. System volume of less than 36 Liters (L), with dimension limits of 595 mm Height x 450 mm Width x 185 mm Depth (greater consideration will be given to lower SWaP, and improved ergonomic designs).

8. Minimum continuous run time in closed circuit mode of three (3) hours threshold (four hours objective), assuming an average of 30 Liters Per Minute (LPM) minute breathing volume.

9. Minimum continuous run time in PAPR mode of four (4) hours threshold (eight hours objective), assuming an average flow rate of 115 LPM for a constant flow system.

10. System maintains breathing gas temperatures under 42 degrees Celsius (°C) throughout operation (greater consideration will be given to designs that provide lower temperatures that enable heat rejection through the breathing air and support greater user comfort).

11. System peak exhalation pressure cannot exceed 200mm of H2O throughout operation.

12. System inhalation pressure may not fall below 0 mm of H2O throughout operation.

13. System uses heat exchange devices other than ice for cooling the breathing loop.

Offerors will provide test data that coincides with domestic safety and regulatory compliance standards to ensure that the system is safe for human operation. Since some domestic regulatory standards for a combined unit respirator do not currently exist in a final form, the offeror will utilize applicable international standards or aspects of standalone mode standards, such as those applicable to PAPR systems and SCBA systems, to ensure safety of operators and maintainers.

Offerors should plan to deliver five (5) working prototypes to be used in an external assessment conducted by the government and provide system familiarization training for the test participants on the operation and use of the prototype system. They will provide technical and logistic support to prototype evaluations, including replenishment of spare parts, replacement of consumables, and repairs of serviceable system components, as required.

The technology developed as part of this effort will contribute to the development of a full spectrum respiratory protection system providing scaled protection to extend operational performance in a CBRN environment.

References:

1. Attachment A, Statement of Standard of NIOSH letter “Acceptance of Applications for the testing and evaluation of Self-Contained Breathing Apparatus for Use Against Chemical, Biological, Radiological and Nuclear Agents”, by Richard W. Metzler, Issued on December 28, 2001. https://www.cdc.gov/niosh/npptl/resources/pressrel/letters/lttr- 122801.html https://www.cdc.gov/niosh/npptl/resources/pressrel/letters/lttr-122801.html https://www.cdc.gov/niosh/npptl/resources/pressrel/letters/lttr-122801.html