PROJECT SUMMARY/ABSTRACT Cognitive impairment, including Alzheimer’s Disease and Related Dementias (ADRD), and cardiopulmonary dysfunction following COVID-19, are components of the chronic syndrome known as Long COVID (LC). LC is an unprecedented public health crisis leading to cognitive, mental health, and functional disabilities for millions of people living in the United States and around the world. Large epidemiologic studies have demonstrated that the risk of ADRD increases multifold in many old and young patients following even mild SARS-CoV-2 infection. Patients with LC also frequently experience profound limitations in physical function and exercise intolerance that, when paired with ADRD, are life altering and result in inability to work and lead a family. Rapidly growing evidence links the clinical manifestations of LC to pathophysiologic mechanisms of abnormal inflammation and immune dysregulation. There is a driving, unmet need for robust clinical trials directly targeting immune dysregulation to reduce ADRD and cardiopulmonary injury related to LC. Our central hypothesis is that immunomodulators may be the most effective treatment for these sequelae of LC. Baricitinib is an immunomodulator (JAK1/2 inhibitor) that is FDA-approved to treat acute COVID-19 infection as well as certain autoimmune chronic diseases like rheumatoid arthritis. JAK1/2 signaling is a cardinal driver of both systemic and neuroinflammation. Our study, the Randomized trial EValuating Baricitinib on pERSistent nEurologic and Cardiopulmonary Symptoms of Long COVID (REVERSE-LC), will enroll 500 patients with LC and cognitive impairment at high risk for long-term ADRD across 4 sites to test the hypothesis that 6 months of baricitinib versus matched placebo will improve neurocognitive and physical function in LC. Aim 1 will measure the trajectory of neurocognitive function at enrollment, 6- and 12-months in baricitinib versus placebo patients using an objective neuropsychological battery as well as patient-reported cognitive function. Aim 2 will measure physical function using cardiopulmonary exercise testing and other functional measures in addition to patient-reported physical symptoms in patients treated with baricitinib versus placebo. Aim 3 will evaluate the effect of baricitinib versus placebo on plasma, cerebrospinal fluid, and neuroimaging inflammatory markers at enrollment, as well as 6- and 12-month follow-up study visits in patients with LC to identify inflammatory mediators of neuropsychological (ADRD) outcomes. The REVERSE-LC trial is novel in targeting immune dysregulation and inflammation for patients with LC and is based on our growing understanding of the mechanism of this emerging, post-infectious cause of rapidly-acquired ADRD risk. Regardless of the outcome of REVERSE-LC, this study will provide crucial insights into treatment of ADRD, sequelae of COVID, and disease pathogenesis. This investigation will also establish an innovative trial platform by which to test future interventions for rapidly-acquired neurocognitive dysfunction, cardiopulmonary disease, LC, and other age- related comorbidities leading to ADRD. It will advance the science of aging brain disease and disability.

PROJECT NARRATIVE After acute COVID-19 infection, millions of patients, both old and young, suffer from a syndrome called Long COVID, which can include months and years of brain dysfunction even after mild infections, placing patients at risk for both “Alzheimer’s disease and/or related dementias” (ADRD) and profound physical disability. Growing evidence indicates that Long COVID’s debilitating brain and body disease is often due to persistent inflammation and new problems of our immune system, but anti-inflammatory or immunomodulator medications have not been adequately studied in patients with Long COVID. The Randomized trial EValuating Baricitinib on pERSistent nEurologic and Cardiopulmonary Symptoms of Long COVID (REVERSE-LC) clinical investigation will enroll 500 patients with Long COVID to determine if baricitinib—an anti-inflammatory and immunomodulator drug that is FDA-approved to save lives in acute COVID-19—improves brain function and physical impairment in patients suffering from Long COVID.