Randomized Double-Blind Placebo-Controlled Trial EValuating Baricitinib on PERSistent NEurologic and Cardiopulmonary Symptoms of Long COVID

INCLUSION CRITERIA:

In order to be eligible to participate in this investigation, an individual must meet all of the following criteria:

Cohort #1 (n=500):

1. Evidence of personally signed and dated informed consent document indicating thatthe participant has been informed of all pertinent aspects of the study and waswilling and able to consent to participation.

2. Age ≥18 years old.

3. Documented SARS-CoV-2 infection 6 or more months prior using an Antigen or NAAT.

4. Clinical evidence of Long COVID, as confirmed by the investigator's assessment: a. At least one symptom (listed below) that is new or worsened since the time ofSARS-CoV-2 infection, not known to be attributable to another cause upon assessmentby the study clinicians (MD, DO, NP, PA, RN, or equivalent). i. Systemic symptoms (e.g., fatigue, chills, post-exertional malaise),neurocognitive symptoms (e.g., trouble with memory/concentration ("brain fog"),headache, dysautonomia/postural orthostatic tachycardia syndrome, dizziness,unsteadiness, neuropathy, sleep disturbance), cardiopulmonary symptoms (e.g., chestpain, palpitations, shortness of breath, cough, fainting spells), musculoskeletalsymptoms (e.g., muscle aches, joint pain), gastrointestinal symptoms (e.g., nausea,diarrhea). Although other symptoms (e.g., skin rash, hair loss, mental healthsymptoms, trouble with smell/taste, genitourinary symptoms) will be recorded andtracked, at least one core symptoms listed above must be present. b. Symptoms must have started after January 2020 and be present for at least 6months prior to screening. Symptoms that wax and wane must have been initiallypresent at least 6 months prior to screening. c. Symptoms must be reported to have an impact on quality of life and/or everydayfunctioning and to be at least somewhat bothersome. d. Symptoms cannot be explained by an alternative diagnosis. e. Cognitive impairmentpresent defined by having at least 20% positive items (answered subjectively worseor much worse) on the 41-item modified ECog questionnaire.

Cohort #2 (n=50):

1. Evidence of personally signed and dated informed consent document indicating thatthe participant has been informed of all pertinent aspects of the study and waswilling and able to consent to participation.

2. Age ≥18 years old.

3. Clinical diagnosis of COVID infection 6 or more months prior a. Clinical Criteria (Based on Council of State and Territorial EpidemiologistsStandardized Surveillance Case Definition for COVID-19): i. At least two of thefollowing symptoms: Fever (measured or subjective), chills, rigors, myalgia,headache, sore throat, new olfactory and taste disorder(s).

-OR- ii. At least one of the following symptoms: Cough, shortness of breath, ordifficulty breathing.

-OR- iii. Severe respiratory illness with at least one of the following: clinical orradiographic evidence of pneumonia or Acute Respiratory Distress Syndrome (ARDS).

-AND- iv. No alternate more likely diagnosis

4. Clinical evidence of Long COVID, as confirmed by the clinician's assessment: a. At least one symptom (listed below) that is new or worsened since the time ofSARS-CoV-2 infection, not known to be attributable to another cause upon assessmentby the study clinicians (MD, DO, NP, PA, RN, or equivalent). i. Systemic symptoms (e.g., fatigue, chills, post-exertional malaise),neurocognitive symptoms (e.g., trouble with memory/concentration ("brain fog"),headache, dysautonomia/postural orthostatic tachycardia syndrome, dizziness,unsteadiness, neuropathy, sleep disturbance), cardiopulmonary symptoms (e.g., chestpain, palpitations, shortness of breath, cough, fainting spells), musculoskeletalsymptoms (e.g., muscle aches, joint pain), gastrointestinal symptoms (e.g., nausea,diarrhea). Although other symptoms (e.g., skin rash, hair loss, mental healthsymptoms, trouble with smell/taste, genitourinary symptoms) will be recorded andtracked, at least one core symptoms listed above must be present. b. Symptoms must have started after January 2020 and be present for at least 6months prior to screening. Symptoms that wax and wane must have been initiallypresent at least 6 months prior to screening. c. Symptoms must be reported to have an impact on quality of life and/or everydayfunctioning and to be at least somewhat bothersome. d. Cognitive impairment present defined by having at least 20% positive items (answered subjectively worse or much worse) on the 41-item modified ECogquestionnaire.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this investigation:

1. Pre-existing cognitive impairment not exacerbated by COVID-19, including but notlimited to syphilis, as determined by study clinicians (MD, DO, NP, PA, RN, orequivalent), which may include a review of participant's history and medicalrecords.

2. Severe cognitive, physical, or psychological disability preventing participation inthe study, as determined by the investigator.

3. Moderate or High risk of suicidality, as determined by the modified Columbia SuicideSeverity Rating Scale (mC-SSRS).

4. History of a major adverse cardiovascular event (MACE) within the 3 months prior toenrollment.

5. Current use of baricitinib or other disease-modifying antirheumatic drug (DMARDs)

6. Known prior allergic reactions to components of the baricitinib.

7. Previously randomized in this study or in the last 30 days have been in anotherstudy investigating baricitinib.

8. Current probenecid use.

9. Positive SARS-CoV-2 NAAT or rapid Antigen test in the 14 days prior to screening.

10. Currently pregnant or breastfeeding or planning to become pregnant or breastfeedduring the course of the study.

11. Venous thromboembolism in the past 6 months prior to screening or felt to be atincreased risk of thrombosis by the investigator.

12. Malignancy or lymphoproliferative disorder not in remission for at least 5 years.Local non-melanoma skin cancers that are definitively managed are not exclusionary.

13. Previous admission to an ICU for treatment of acute COVID-19 infection.

14. Estimated glomerular filtration rate of < 30 mL/min/1.73m2, as calculated using theCKD-EPI 2021 equation.

15. Absolute Neutrophil Count (ANC) <1000 cells/mm3, confirmed on repeat testing.

16. Absolute Leukocyte Count (ALC) <100 cells/mm3.

17. Evidence of severe liver disease at the time of screening, defined as Bilirubin > 1.5 X ULN or AST or ALT > 2x ULN.

18. Alkaline Phosphatase (ALP) ≥ 3x ULN.

19. Creatine Phosphokinase (CPK) ≥ 3x ULN.

20. Hemoglobin (HgB) < 8 g/dL, confirmed on repeat testing.

21. Platelets <100,000 cells/mm3, confirmed on repeat testing.

22. Platelets >500,000 cells/mm3, confirmed on repeat testing.

23. Total fasting cholesterol ≥ 280 mg/dL, confirmed on repeat testing.

24. Fasting LDL ≥ 180 mg/dL, confirmed on repeat testing.

25. Positive Hepatitis B surface antigen or Hepatitis B core antibody. Note: Individualswith a positive Hepatitis B core antibody will be excluded even in the presence of apositive Hepatitis B surface antibody due to the risk of reactivation.

26. Positive for Hepatitis C at the time of Screening. Note: treated or clearedHepatitis C is not exclusionary.

27. Symptomatic herpes zoster infection (i.e., visible herpetic skin lesions of Zoster)within 3 months prior to study screening, or any history of disseminated/complicatedherpes zoster or herpes simplex infection (e.g., VZV encephalitis).

28. History of untreated latent tuberculosis infection (diagnosed with QuantiFERON-TBGold Plus testing) or active tuberculosis whether treated or untreated. Note: thosewith a positive PPD who have a history of BCG vaccine and a negative QuantiFERON-TBGold Plus test will remain eligible).

29. History of current or recent (< 30 days from screening) sepsis or clinicallysignificant viral, bacterial, fungal, or parasitic infection, according to thedetermination of the investigator.

30. Participants with HIV will be excluded if they have been on ART <1 year, have a CD4+T cell count <500 cells/ml (confirmed on repeat), or have two consecutive HIV plasmaRNA viral load > 48 copies/mL within 1 year of study screening, including requiringthe most recent within 3 months of screening. Blips (VL > 48 copies/mL but < 200copies/mL) are permitted if preceded and followed by values below the assay limit ofquantification.

31. Immunocompromised as defined by NIH COVID-19 guidelines (see Appendix) and, in theopinion of the investigator, at an unacceptable risk for participating in the study.

32. Treatment with another investigational drug or device as part of an interventionalstudy within 30 days of study screening.

33. In the opinion of the investigator, unable to reliably follow-up for the duration ofthe study and/or are unable to follow study restrictions/procedures.

34. Persons of childbearing potential under age 55 who are unwilling or unable toabstain from sex or to use at least one acceptable method of contraception from thetime of screening though at least 28 days after the end of the study interventionperiod. Note: Acceptable methods include barrier contraceptives (condoms ordiaphragm) with spermicide, intrauterine devices (IUDs), other contraceptives, oralcontraceptive pills, and surgical sterilization. Participants unwilling to becounseled about risks related to pregnancy or breastfeeding.

35. Participants actively breastfeeding, who are unwilling to stop breastfeeding for theduration of the trial.

36. Currently incarcerated

NOTE RE: History of major adverse cardiovascular event (MACE) or traditional risk factors including smoking. For REVERSE-LC, MACE is defined as acute myocardial infarction and stroke. The study team will discuss the risks and benefits of baricitinib and CV events with the participant prior to study entry.

NOTE RE: EBV/CMV Seropositivity - The investigators will not exclude participants based on EBV or CMV seropositivity. The investigators already know that serologic evidence suggesting recent EBV reactivation is associated with Long COVID fatigue and high level EBV responses are associated with neurocognitive Long COVID, but that EBV viremia and IgM is rare. The investigators believe there is equipoise with regard to the potential effects of baricitinib on EBV - it is as likely that inflammation drives EBV reactivation, just as EBV can drive inflammation. For this reason, the investigators think this is best studied as a biological factor correlated with outcomes and that the investigators should not deliberately include or exclude people based on this. CMV seropositivity is associated with improved Long COVID outcomes. Results are not required for screening.