# REVERSE-Long COVID: A Multicenter Randomized, Placebo-Controlled Clinical Trial of Immunomodulation (with Baricitinib) for Long COVID Related ADRD

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $5,665,215

## Abstract

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...

## Key facts

- **NIH application ID:** 10827260
- **Project number:** 1R01AG085873-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** E Wesley ELY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $5,665,215
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827260

## Citation

> US National Institutes of Health, RePORTER application 10827260, REVERSE-Long COVID: A Multicenter Randomized, Placebo-Controlled Clinical Trial of Immunomodulation (with Baricitinib) for Long COVID Related ADRD (1R01AG085873-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10827260. Licensed CC0.

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