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Clinical Trials: Viral Diseases
IRB No. 20-192-2.F (Dr. Bruce Liang, PI): A randomized, open-label study of the vascular and microbiologic efficacy of dipyridamole plus standard care vs. standard care in hospitalized COVID19 patients.
Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). In severe illness, COVID 19 infection results in lymphopenia, elevated D-dimer levels, hypercoagulation, hypertension, acute respiratory distress syndrome (ARDS), and acute cardiac injury. Dipyridamole (DIP) is an FDA- approved drug which inhibits adenosine uptake that leads to increased extracellular adenosine which in turn stimulates adenosine receptor mediated vasodilatory, anti-platelet and anti-inflammatory effects. These effects are also augmented by DIP's inhibition of phosphodiesterase. In addition, DIP appears to bind to the HCoV-19 protease enzyme and also suppresses HCoV-19 proliferation in Vero E6 cells with an IC50 less than or equal to 100 nM. Plasma concentrations in humans from routine dosing regimens (regimen of 50 mg three times per day) exceed this IC50 value for the duration of the dosing interval. In vivo anti-viral effect for DIP, very recently has been demonstrated in vesicular stomatitis virus-induced pneumonia with prolongation of survival (1). There is limited clinical data on dipyridamole in COVID-19 patients. At this writing, the remdesivir and hydroxychloroquine are now approved for investigations, by the FDA to treat these patients. Although the exact mechanism by which these drugs may work in this infection is not known, DIP exerts its potential salutary effect via different mechanism. In a preliminary, un-randomized trial with a small number of COVID19 patients treated with prophylactic anticoagulation therapy (Hubei China, January 2020) --the addition of DIP led to increased platelet and lymphocyte counts with reduced D-dimer level, compared to standard of care patients (1). Additionally, 2 weeks after DIP treatment of 12 patients, 3 of the severe cases and all 4 of the mild-to-moderate cases were discharged from the hospital. One patient died while 3 remaining patients were in remission in the hospital. In the control group, 3 of the 3 mild-to-moderate cases and 1 of 4 severe cases were discharged and only 1 was in remission in the severe group with 1 death. However, the trial was not randomized and was small in size, hence there was no statistical analysis for clinical outcomes. 100 will be enrolled with in an open label, randomized controlled trial with 50 being randomized to receive dipyridamole, 100 mg tid for 7 days being added to Standard Care. (1). Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction Xiaoyan Liu, Zhou, Hai-Bin Luo, et. al doi: https://doi.org/10.1101/2020.02.27.20027557
IRB No. 21-070J-1 (Dr. George Kuchel, PI): Dynamic assessment of immune system in COVID-19 patients: Flu Vaccine Pilot Study 1
This prospective, single-site pilot study is designed to determine the feasibility to recruit and enroll COVID-19 convalescent adults into a study that will assess immunity changes associated with aging. To complete a 12 subject pilot study with the following aims: To establish feasibility of conducting a larger trial with the enrollment of COVID-19 convalescent adults, we will enroll 6 older (65 years and older) and 6 young (25-50 years) adults that have recovered from COVID-19. To gather preliminary data on epigenomic signatures of responsiveness to the seasonal influenza vaccine in adults recovered from COVID-19. To gather preliminary data on microbiome signatures of COVID-19 sequelae. The objective of this project is to systematically identify the most relevant factors that are associated with the prolonged effects of COVID-19 on immunity by applying a systems immunology approach that incorporates high-resolution immunologic assays with state-of-the-art genomic, proteomic, metabolomic assays. Major questions we will address include: i) which immune cell types and gene expression programs are remodeled with COVID-19 in the long term?; ii) do these immune alterations associate with changes in vaccine responsiveness?; iii) do COVID-19 sequelae differ between older and younger adults, and between men and women?; iv) are there multi-omics biomarkers of reduced immunity due to COVID-19? To answer these questions, we will establish a longitudinal cohort of young (25-50 yrs old) and older adults (≥65 yrs) who recovered from COVID-19 and we will characterize their immune systems in detail under baseline and upon influenza vaccination.
IRB No. 21-149J-1 (Dr. George Kuchel, PI): High-resolution single cell profiling of SARS-CoV-2 vaccine responsiveness in healthy adults
This study is a collaboration between The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT and UConn Health in Farmington, CT. All recruitment, enrollment, clinical data, and sample collection will occur at the UConn Center on Aging (COA) or at the Clinical Research Center (CRC), under the direction of Dr. George Kuchel, Professor of Medicine and Director of the UConn COA. This prospective, single-site, multi-cohort observational study is designed to determine how vaccine formulations and subject age affect immunologic responses to SARS-CoV-2 vaccine and to uncover the molecular signatures (genomics) elicited by novel COVID-19 vaccines. Up to 114 SARS-CoV-2 naïve healthy men and women aged 21 years or over, from all races and ethnic backgrounds that receive the Pfizer/Moderna/J&J COVID-19 vaccine will be enrolled to this study over a one-year period. Participation will involve nine (9) study visits for adults receiving the two-dose Pfizer or Moderna vaccine and seven (7) study visits for adults receiving the single-dose J&J vaccine. Blood samples (at all 9/7 visits) and nasal swabs (at three visits) will be collected.
IRB No. 22-179J-1 (Dr. George Kuchel, PI): A deep longitudinal analysis of next generation influenza vaccines in older adults
This study is a collaboration between The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT and UConn Health in Farmington, CT. All recruitment, enrollment, clinical data, and sample collection will occur at the UConn Center on Aging (COA), at UConn Health in Farmington, CT under the direction of Dr. George Kuchel, Professor of Medicine and Director of the UConn COA. Coded samples collected at Visits 1-17 will be securely transported to the Jackson Laboratory for Genomic Medicine (JAX), located on the UConn Health campus, for processing, storage, sequencing, and analysis. Dr. Duygu Ucar will oversee sample management and sample and data analysis per protocol. In this study, a total of sixty (60) healthy adults aged 65 years and older who have had no history of confirmed COVID-19 and have not received influenza vaccination for the approaching influenza season will be enrolled in the study and vaccinated with influenza vaccines approved by the U.S Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) for individuals ≥65 years. All participants receive influenza vaccine during the 2022-23, 2023-24, and 2024-25 influenza seasons. Participants will receive Fluzone® Quadrivalent High-Dose vaccine during the 2022-23 and 2024-25 flu seasons and FLUAD® Quadrivalent during the 2023-24 flu season. Blood samples will be collected from the participants at each of the seventeen study visits over three years. Nasal swab and stool samples will also be collected from participants at 7 time-points across the study period. The study is not designed to assess safety or tolerability of the influenza vaccines administered as part of this proposed study. By performing comprehensive profiling of their blood antibodies and immune cells over time, we will be able to associate specific age-related immune alterations with vaccine responder or non-responder status, thus allowing us to pinpoint biological pathways that can be targeted to enhance vaccine efficacy and that can also help us to progress towards developing a universal influenza vaccine.