David W. Wright, MD - US grants

DESCRIPTION (provided by applicant): There are about 5.3 million people in this country living with a range of disabilities caused by traumatic brain injury, and about 25-30% of those people are unable to return to work one year later. At present, there are no effective clinical treatments currently available to the victims of traumatic brain injuries that can repair the primary and secondary damage caused by the cascade of cytotoxic damage unleashed by the initial insult. Obviously, a safe, low cost and effective treatment for such a significant health problem is worth addressing. Numerous reports have documented the role of neurosteroids in immediate post-injury neuroprotection. However, few studies have examined the effect of these steroids as a treatment after the acute phase. We are particularly interested in the effect of progesterone long-term because it is currently being tested in a human clinical trial as an acute phase neuroprotectant. Extensive preclinical trials have shown that progesterone is neuroprotective when administered shortly after injury. However, at least two of the potential mechanisms (inhibition of NMDA transmission and stimulation of GABAA receptors), by which progesterone exhibits neuroprotection, could potentially worsen subacute rehabilitation and subsequent long-term recovery. Conversely, pregnenolone, the precursor of progesterone, exhibits opposite effects with respect to NMDA and GABAA modulation and could enhance neurorehahilitation. We propose to determine the effects of progesterone and pregnenolone when treatment is delayed after injury in animals. The data gathered would provide information regarding the potential utility of these neurosteroids in subacute or long-term treatment conditions. In addition, should progesterone prove to be an effective neuroprotectant in the human clinical trial, it will be necessary to know how long treatment should be maintained and whether long-term treatment enhances or deters post-injury rehabilitation. There is a growing body of evidence that both progesterone and pregnenolone can also stimulate remyelination of damaged nerve cells and that they also have the potential to stimulate neuronal repair after the initial injury cascade has long subsided. This means that these steroids, both of which are synthesized in the brain, may be beneficial as adjunct therapies for long-term rehabilitation. We propose to investigate the role of the neurosteroids progesterone (PROG) and pregnenolone-sulfate (PREGS) as putative treatment for traumatic brain injury during the rehabilitation phase of recovery in both male and female subjects. Therefore, we will examine two delayed treatment paradigms (7 days & 28 days post injury) on the recovery process at the behavioral and morphological levels of analysis.

DESCRIPTION (provided by applicant): This application seeks to establish a training program in trauma care and injury control research in the Republic of Mozambique. It is built on a preexisting partnership between a US University (Emory University) and a Mozambican University (University Eduardo Mondlane or UEM). Mozambique is a southern African nation with a significant healthcare burden related to injury, and with minimal current clinical or research infrastructure to strengthen the care of injured patients. Three stages of training are described in this application: formal academic training, bridge fellowships in the U.S., and subsequent in-country research. The formal academic training is based on the core MPH curriculum currently taught at UEM, supplemented with focused courses in Trauma Care, Violence and Injury Prevention, and a distance education course in Epidemiology. In addition, the University of South Africa (UNISA), Institute for Social and Health Sciences, has agreed to serve as a regional resource for trainees, offering additional focused injury coursework on an elective basis. The Bridge Fellowships at Emory will function as "mini-sabbaticals" to nurture research protocols and provide training in the ethical, legal and social implications of research. Finally, trainees will return to Mozambique to undertake in-country research supported by small startup grants to help trainees launch their first project with ongoing mentorship. Close follow-up and collaboration will be provided during all three phases, and on an ongoing basis. While some trainees will undertake all 3 phases of the training, others may require only select phases (perhaps spending more time at UNISA in supplemental courses, or spending more time on in-country research). Evidence of strong in-country support is presented. This plan has several advantages: it is highly cost-effective, it relies on the strengths of two WHO collaborating centres for injury control (Emory and UNISA), it uses a regional or "south to south" training approach, in-country supplemental training will reach others beyond our core trainees, it signals Emory's intent to Mozambique to be a long-term partner in building the nation's capacity to conduct high quality research in trauma care and injury control, and it lays the foundation for a regional collaborative that could ultimately lead to expansion of this trauma and injury control research beyond Mozambique to include other nations in Southern and East Africa.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide. With the possible functional outcomes. We recently completed an NINDS-funded, Phase l/lla double-blinded, randomized placebo-controlled pilot clinical trial examining the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective properties in multiple different animal models of brain injury. Based on encouraging results, we propose to conduct a phase III clinical trial to determine the efficacy and confirm safety of this treatment in adults with moderate to severe TBI. [unreadable] Our primary objective is to determine the effectiveness of intravenous progesterone initiated within 4 hours of injury and administered for 72 hours, followed by an additional 24 hour taper, as compared to placebo at improving functional outcome in patients with moderate to severe traumatic brain injury. The primary functional outcome will be determined by Glasgow Outcome Scale - Enhanced (GOSE) measured at 6 months after injury. Secondary objectives are to examine the effects of progesterone versus placebo on mortality, intracranial pressure, alternative measures of functional neurological outcome, on rates of adverse events, and examine the effectiveness in 5 clinical subgroups in patients with moderate to severe TBI. In order to proceed towards the Phase III clinical trial, we are submitting a clinical trial planning grant. The specific objectives of the planning grant are to complete a Manual of Operations; identify, recruit and certify participating centers; assess each candidate center's ability to enroll eligible patients; develop a MCCT data management plan; complete study materials and generate study forms; prepare training schedules and materials; establish committees and organizational chart; prepare budgets and cooperative agreements: develop a model IRB protocol, work with local IRBs to implement Exception from Consent; and obtain FDA IND final approval for intravenous use of progesterone to treat acutely brain-injured adults with an Exception from Informed Consent. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Our objective is to participate in the Neurological Emergencies Treatment Trials (NETT) network in order to improve outcomes for patients with neurological emergencies. Our goals align with those of the NETT. The NETT Southeastern Collaborative will 1) facilitate high-quality clinical trials in a wide variety of neurological diseases (cerebrovascular disorders, epileptic seizures, acute infections of the CNS, acute neuromuscular disorders and trauma) in adults or children; 2) build on existing and create new collaborations between emergency medicine physicians, neurologists, neurosurgeons, trauma specialists, neuroradiologists, and neuro-intensivists in the development and conduct of clinical trials, 3) facilitate the implementation of new therapies into clinical practice by active collaborations with community and local hospitals. We have active collaborations with many of these hospitals, a majority of which have emergency medicine and neurology faculty residency trained at our own program at Emory University. Our Specific Aims are: 1. To develop an infrastructure to conduct clinical trials in neurological emergencies. 2. To develop a regional collaborative network of high volume hospitals capable of conducting efficient and high quality clinical trials. 3. To recruit a broad range of participants, particularly minorities. 4. To facilitate the transfer of research results to clinical practice, especially to community hospital settings, and the general endorsement by emergency medicine physicians. The NETT SEC brings together an extensive array of high volume urban and sub-urban hospitals with a well established tract record of expertise and experience in conducting ground breaking research in neurological emergencies in a multiracial region. [unreadable] [unreadable]

Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide. No therapy has been effective in reducing mortality and improving functional outcomes. We recently completed an NINDS-funded, Phase I/IIa double-blinded, randomized placebo-controlled pilot clinical trial examining the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective properties in multiple different animal models of brain injury. Based on the extensive preclinical evidence of activity and the promising findings of our pilot study we propose to conduct a phase III clinical trial to definitively assess the efficacy of this treatment for adults with moderate to severe acute TBI. Our primary objective is to determine the effect of administering intravenous progesterone (initiated within 4 hours of injury and administered for 72 hours, followed by an additional 24 hour taper) versus placebo for treating victims of moderate to severe (GCS 12-4) TBI. Our secondary objectives are to examine the effects of progesterone vs. placebo in patients with moderate to severe TBI on 6 month mortality, Disability Rating Scale score, cognitive, neurological and functional outcome using a select battery of tests, and the rates of adverse and severe adverse events. If the therapeutic benefits observed in animals and from our pilot study are replicated, administration of intravenous progesterone should decrease mortality and improve neurological function. Positive results would represent a major advance in the treatment of TBI.

DESCRIPTION (provided by applicant): The Emory Neurological Emergencies Treatment Trials - Southeastern Collaborative (NETT-SEC) is a productive member of the NETT network. The NETT-SEC has participated in all NETT trials and is in the top 1/3rd for enrollments in RAMPART, ALIAS, and ProTECT III, accounting for over 148 subjects enrolled into the NETT trials (as of 11/14/2011). The goal of the NETT-SEC is synchronous with the NETT's overall stated purpose: to conduct large streamlined phase III clinical trials in a broad spectrum of neurological emergencies in order to reduce the morbidity and mortality of neurological diseases. We have participated in all of the NETT studies and contributed pediatric and adult subjects from all races and ethnicities. The NETT-SEC has formed extensive and highly functional collaborations with emergency medicine, neurology, neurointensive care, interventional neuroradiology, radiology, neurosurgery, anesthesiology, trauma surgery, pharmacology, ethics, biomedical engineering, laboratory science, neuropsychology, neuro-ophthamology, orthopedics (spine), EMS, Industry (Banyan Biomarkers), and others. In addition, the NETT-SEC brings together an extensive array of high volume urban and suburban hospitals with a well-established track record of expertise and experience in conducting ground-breaking research in neurological emergencies in a multiracial region. AIMS: 1.Continue high enrollment of a diverse population of subjects in NETT-sponsored Clinical Trials; 2. Grow the NETT-SEC by expanding collaborations, training programs, student and faculty mentoring, and community outreach; 3. Facilitate neurological emergencies research by enhancing NETT operations, expanding the NETT research portfolio, contributing to the dialog on research ethics, and disseminating discoveries to the community. The NETT-SEC has a proven track record as a productive hub of the first NETT network and will continue to support the goals of the NETT and NINDS by conducting high quality, efficient. Phase III clinical trials in both academic and community settings.

The CORE-EM Alliance (COalition for REsearch in Emergency Medicine) brings to SIREN six highly experienced research infrastructures, each with their own 5 spokes, partnering to create an innovative single super hub in the 10-hub SIREN network. The goal of CORE-EM is to provide a highly functioning infrastructure for rapid implementation and high quality performance of large pragmatic clinical trials for a wide variety of emergency conditions including, neurology, cardiovascular, respiratory, hematologic, and trauma related emergencies. Our model is remarkably flexible and efficient, as we can be as lean as six independent sites, or have the ability to rapidly expand to 30-plus enrolling sites. The CORE-EM leverages veteran leadership and experienced research teams with a long history of prior successful collaboration and exemplary clinical trial performance and provides SIREN access to an impressively diverse patient population, spanning large geographic regions within the Southern and Eastern United States. The CORE-EM Alliance will easily be capable of implementing four or more simultaneous large (>1,000 patient), simple, pragmatic trials in the Emergency Department (ED) and out of hospital settings. CORE-EM is committed to being an extraordinary partner for SIREN with a focus on conducting rigorous trials and assessments of novel therapeutic interventions in an aim to improve the lives of our patients.  

The Specific Aims of this proposal are to: : 1) enhance the successful mission of the Georgia StrokeNet by accelerating recruitment into NIH StrokeNet clinical trials for patients with acute stroke, people at risk for recurrent stroke and individuals recovering from stroke; 2) develop and propose new and innovative clinical trials in stroke to be conducted within the NIH StrokeNet; and 3) enhance the training opportunities for promising young investigators interested in clinical stroke research as a career. As a currently-funded NIH StrokeNet Regional Coordinating Center (RCC), the Georgia StrokeNet brings an established infrastructure of highly successful and collaborative investigators and coordinators, with many years of proven expertise in designing, conducting, and enrolling patients into randomized clinical trials across the continuum of stroke care, from pre-hospital through rehabilitation. Our RCC has demonstrated the ability to quickly implement research protocols using master trial agreements and a central IRB, and has brought to the existing network strong leadership skills, as evidenced by our team members? active and ongoing participation in NIH StrokeNet working groups including Co-Chair of the NIH StrokeNet?s Rehabilitation working group and the only Project Coordinator representation in the Acute Stroke Working Group since implementation. Emory?s Georgia StrokeNet proposal builds upon our RCC?s track record of 5 years of highly successful participation as an NIH StrokeNet site, 10 years as a top enroller for the NINDS-sponsored Neurological Treatment Trials Network (NETT), recent selection as one of only 11 hubs for the NIH-funded SIREN (Strategies to Innovate EmeRgENcy Care) Clinical Trials Network, and a 25 year history of high enrollment in multiple NIH and industry sponsored practice changing randomized clinical trials in stroke.

The CORE-EM Alliance (COalition for REsearch in Emergency Medicine) brings to SIREN six highly experienced research infrastructures, each with their own 5 spokes, partnering to create an innovative single super hub in the 10-hub SIREN network. The goal of CORE-EM is to provide a highly functioning infrastructure for rapid implementation and high quality performance of large pragmatic clinical trials for a wide variety of emergency conditions including, neurology, cardiovascular, respiratory, hematologic, and trauma related emergencies. Our model is remarkably flexible and efficient, as we can be as lean as six independent sites, or have the ability to rapidly expand to 30-plus enrolling sites. The CORE-EM leverages veteran leadership and experienced research teams with a long history of prior successful collaboration and exemplary clinical trial performance and provides SIREN access to an impressively diverse patient population, spanning large geographic regions within the Southern and Eastern United States. The CORE-EM Alliance will easily be capable of implementing four or more simultaneous large (>1,000 patient), simple, pragmatic trials in the Emergency Department (ED) and out of hospital settings. CORE-EM is committed to being an extraordinary partner for SIREN with a focus on conducting rigorous trials and assessments of novel therapeutic interventions in an aim to improve the lives of our patients.  

The Specific Aims of this proposal are to: : 1) enhance the successful mission of the Georgia StrokeNet by accelerating recruitment into NIH StrokeNet clinical trials for patients with acute stroke, people at risk for recurrent stroke and individuals recovering from stroke; 2) develop and propose new and innovative clinical trials in stroke to be conducted within the NIH StrokeNet; and 3) enhance the training opportunities for promising young investigators interested in clinical stroke research as a career. As a currently-funded NIH StrokeNet Regional Coordinating Center (RCC), the Georgia StrokeNet brings an established infrastructure of highly successful and collaborative investigators and coordinators, with many years of proven expertise in designing, conducting, and enrolling patients into randomized clinical trials across the continuum of stroke care, from pre-hospital through rehabilitation. Our RCC has demonstrated the ability to quickly implement research protocols using master trial agreements and a central IRB, and has brought to the existing network strong leadership skills, as evidenced by our team members? active and ongoing participation in NIH StrokeNet working groups including Co-Chair of the NIH StrokeNet?s Rehabilitation working group and the only Project Coordinator representation in the Acute Stroke Working Group since implementation. Emory?s Georgia StrokeNet proposal builds upon our RCC?s track record of 5 years of highly successful participation as an NIH StrokeNet site, 10 years as a top enroller for the NINDS-sponsored Neurological Treatment Trials Network (NETT), recent selection as one of only 11 hubs for the NIH-funded SIREN (Strategies to Innovate EmeRgENcy Care) Clinical Trials Network, and a 25 year history of high enrollment in multiple NIH and industry sponsored practice changing randomized clinical trials in stroke.

PROJECT SUMMARY In the US, it is estimated that there are over 3.8 million traumatic brain injuries (TBI) annually, which account for approximately 2.5 million emergency department visits each year. For children 14 years of age and younger, there were approximately 640,000 TBI-related emergency department (ED) visits in 2013 [CDC 2018]. Over 80% of TBI is classified as mild (mTBI), with the term concussion used interchangeably [McCrory et al., 2017; Menon et al., 2010]. In addition to EDs, urgent care centers and primary care physicians are also charged with the initial evaluation and management of patients seeking care for mTBI. Despite the benign sounding term, mTBI often has significant short and long-term consequences that can be modified by early identification, intervention and management (Yang et al., 2017; Collins et al., 2016). However, the system of care is fragmented and clinician training on appropriate evaluation, coordination of care and management is limited. To overcome these limitations, the primary aim of this study is to demonstrate that evidence- based practice and education for the patient, caregivers, clinical providers and schools is feasible and will promote recovery following a mild TBI in children and adolescents. We have developed an evidence/best-practices based TBI Evaluation and Management (TEaM) Toolkit aimed at key providers in the system of mTBI healthcare. The TEaM Toolkit leverages the electronic medical record system (eMR) and a targeted training program to improve screening, management, and linkage throughout the continuum, or what we refer to as the neighborhood of care, with a goal of producing an effective and scalable toolkit to promote recovery. !