INVESTIGATOR(S): Facilitated by Daniel F. Hanley, Jr., MD and the National Center for Advancing Translational Sciences (NCATS) Johns Hopkins-Tufts Trial Innovation Center; David J. Sullivan, MD (Co-PI); Shmuel Shoham, MD (Co-PI)
SUMMARY: This randomized, blinded phase 2 trial will assess the efficacy and safety of Anti- SARS-CoV-2 convalescent plasma as prophylaxis following exposure to COVID-19. 150 subjects aged 18 years of age and older who have experienced a close contact exposure to a person with COVID-19 in the past 120 hours AND have not yet themselves developed symptoms of COVID-19 will be evaluated over a 2 year time period after either receiving anti-SARS-CoV-2 convalescent plasma or placebo. Patients identified as having recovered from COVID-19 will serve as potential donors. Donors with SARS-CoV-2 antibody titers ? 1:320 by validated ELISA will be used for the trial.

INVESTIGATOR(S): Ellen Mowry, MD (Co-PI); Kathryn C. Fitzgerald, ScD (Co-PI)
SUMMARY: This patient-centered study would draw from Johns Hopkins patients seen in the last three years for multiple sclerosis (MS), neuromyelitis optica (NMO), autoimmune neuromuscular diseases, sarcoidosis, inflammatory bowel disease, rheumatologic disease. Patient surveys – weekly for the first three months followed by monthly – on demographics, disease-modifying and concomitant medication use, social distancing/employment during the pandemic, comorbidities, COVID-19 symptoms would be the tool to build a data set. This metadata could be analyzed for disease-specific trends at Johns Hopkins and compared to other institutions in the United States, as well as to compare risk and severity across types of immune suppression and other risk factors.

INVESTIGATOR(S): Arun Venkatesan, MD, PhD (Co-PI); John C. Probasco, MD (Co-PI); Romergryko G. Geocadin, MD (Co-PI); Carlos A. Pardo-Villamizar, MD (Co-PI); Matthew J. Elrick, MD, PhD (Co-PI); Wendy Ziai, MD, MPH (Co-PI)
SUMMARY: Over the past decade, we have been at the forefront of characterization of neurologic manifestations, associated biomarkers, and burden of acute encephalitis (summarized, for example, in Venkatesan et al. Lancet 2019; our work includes the study of respiratory virus-associated encephalitis- see for example Beattie et al., Clinical Infectious Diseases 2013). We plan to utilize our pre-existing infrastructure to study COVID-19 neurologic infection and acute associated neurologic complications. The hypothesis is that a subset of patients will develop acute necrotizing encephalopathy (ANE), an entity characterized by deep gray matter injury following respiratory virus infection; and that this will correlate with higher levels of serum and CSF cytokines than other COVID-19 + patients.

Type: Clinical
INVESTIGATOR(S): Arun Venkatesan, MD, PhD (Co-PI); John C. Probasco, MD (Co-PI); Carlos A. Pardo-Villamizar, MD (Co-PI); Adam Kaplin, MD, PhD (Co-PI); Christian A. Merlo, MD, PhD (Co-PI)
SUMMARY: We have a deep interest in understanding the neurologic consequences of central nervous system (CNS) infections and have recently completed the largest study of its kind (>600 patients) on sequelae following encephalitis. We plan to utilize our infrastructure to characterize long-term neurologic sequelae (including cognitive, neurobehavioral, fatigue, headache, and dysautonomia) in post-COVID patients. The hypothesis is that patients with CNS involvement of COVID-19 and/or evidence of increased cerebrospinal fluid (CSF) pro-inflammatory cytokines or injury per radiographic findings during acute disease will be at greater risk for long-term neurologic sequelae.

INVESTIGATOR(S): Chetan Bettegowda, M.D., Ph.D.
SUMMARY: COVID-19 causes severe disease in a subset of patients by inducing unusually strong immune response. Previous work by the group has identified a drug* which is already FDA-approved and in broad use to treat enlarged prostate glands, can dampen the abnormal immune response induced by several diseases similar to COVID-19.
The hypothesis is that by tamping down the immune system’s unusually strong response to the virus, this particular drug can prevent infected patients who have mild symptoms from progressing to severe disease. The research team has developed a clinical trial protocol designed to determine whether this drug can halt the progression of mild COVID-19 to severe disease. Patients infected with COVID-19 who only have mild symptoms will be divided into two groups; one group will be treated with the drug, and the other group will receive standard medical care. The proportion of patients progressing to severe disease, such as requiring breathing machine or death, will be compared. The trial will also test biomarkers in the blood to establish tests that can predict the development of severe COVID-19. A number of other medical centers including Catholic University in Rome, Italy, and Brown University in Providence, RI expressed interested in running our clinical trial protocol. Discussions continue with academic centers worldwide.
A second part of the study will include analyzing records from millions of Americans over the past 5-10 years who have diseases similar to COVID-19 to identify other shelf-ready drugs that have the potential of being rapidly repurposed to treat COVID-19. Preliminary analysis of one such administrative health care database has shown that patients with acute respiratory distress syndrome (ARDS), similar to what is seen in advanced COVID-19, were 50% less likely to die if they were taking this specific drug before they got sick. This suggests that this specific drug studied and other drugs within this specific classification may be effective in COVID-19 but this needs to be further tested in rigorous clinical trials. *Note: The name of the drug has been omitted to protect current drug supply.

INVESTIGATOR(S): Shenandoah Robinson, M.D.
SUMMARY: Our overarching goal is to prevent debilitating COVID-19 sequelae using neuro-immunomodulatory therapies. Specifically, we propose to test a cocktail of neurorestorative medications. SARS-CoV-2 infection causes brain injury by two mechanisms: 1) direct invasion of brain cells via the ACE2 receptors, and 2) secondary injury mediated by the peripheral inflammatory response, the focus of this proposal. We hypothesis that those who suffer a severe illness with SARS-CoV-2 infection, especially those with pre-existing conditions, have a baseline hyper-reactive immune system that propagates neuroinflammation following peripheral cytokine surges.
We predict combination pharmacotherapy that capitalizes on endogenous neurorestoration will safely mitigate chronic neurological sequelae from COVID-19. We propose to use a combination of melatonin (MLT) and propyl hydroxylase domain inhibitors (PHDI) to modulate neuroinflammation and prevent neurological deficits after serious illness from COVID-19. We have shown in multiple preclinical models of brain insults that monotherapy with either EPO or MLT is only mildly effective compared to combinatorial therapy. We propose treatment with a sustained, safe course of PHDI+MLT during COVID-like illness to prevent neurological deficits from chronic neuro-inflammation.
To mimic inflammation from pre-existing conditions, we prime the immune system in rats with systemic injection of bacterial lipopolysaccharide. Currently, we are using subsequent poly(I:C) injection to replicate viral infection with COVID-19. When CRISPR-Cas9 rats with humanized ACE2 receptors become available, we will transition to using them as our model system, with SARS-CoV-2 spike protein to instigate systemic illness. To date, to mimic differences in response to SARS-CoV-2 infection across the lifespan, we have developed four models: perinatal, juvenile, middle-age and older adult.
We propose two Aims: Aim 1: Investigate differences in serum and brain inflammatory pathways across four ages in response to PHDI+MLT treatment after poly(I:C) illness induction. We will use a combination of peripheral blood monocyte cell stimulation assays, multiplex electrochemiluminescent assays, flow cytometry and single-cell RNAseq to quantify inflammatory signatures. We predict immune responses will vary by age, and that all ages will show attenuation of peripheral and brain damaging neuroinflammation with PHDI+MLT treatment. Aim 2: Investigate whether PHDI+MLT treatment prevents chronic cognitive deficits and pain. We will use highly translational touchscreen platforms, similar to those used to test cognition in humans, to measure executive function and attention. We will also define chronic pain phenotypes by assaying for mechanical allodynia, thermal hypersensitivity and late phase formalin response. These results will be correlated with advanced tractography using diffusion tensor imaging and functional brain MRI. We predict robust correlation between neurorestoration of cognition and pain, and imaging outcomes. While many questions will remain from these initial studies, we expect to have data to justify early translation to clinical trials.