The overarching goal of this study is to determine if baricitinib, as compared toplacebo, will improve neurocognitive function, along with measures of physical function,quality of life, post-exertional malaise, effect of breathlessness on daily activities,post-COVID-19 symptom burden, and biomarkers of inflammation and viral measures, inparticipants with Long COVID.
Since the emergence of the severe acute respiratory syndrome coronavirus 2 pathogen in
late 2019, there have been over 680 million cases worldwide and over 6 million deaths. In
the United States alone, there have been over 100 million cases and over 1 million
deaths. Both novel vaccines and effective therapeutics have helped reduce mortality in
well-resourced countries. Despite these advances, millions of patients subsequently
experience a devastating post-acute infection syndrome known as post-acute sequelae of
SARS-CoV-2 infection (PASC), or better known by patients as Long COVID (LC). In the
United States alone, it is estimated that up to 18 million adults suffer from LC with
persistent neurocognitive impairments (NCI) and cardiopulmonary symptoms such as dyspnea
and exercise intolerance for months to years after acute COVID-19. Additionally, up to 1
in 5 patients who were working prior to contracting SARS-CoV-2 may not return to the
workforce due to cognitive and physical impairments. The public health burden of LC is
estimated to be the largest seen from an emerging disease in the last 100 years, yet
there are currently no effective interventions.
These clear and objective changes in cognitive function and brain structure highlight the
devastating and long-lasting effects of SARS-CoV-2 infection on survivors' long-term
health, highlighting the need for effective therapies to improve long-term cognitive
outcomes.
In addition to the devastating NCI that patients with LC experience, many survivors go on
to experience activity-limiting dyspnea on exertion, exercise intolerance, and reduced
physical function. In fact, patients who have not fully recovered physically 5 months
after infection may fail to recover further by one year. Patients with LC experience
significant self-reported physical symptoms including persistent fatigue and dyspnea as
well as objective impairments in exercise capacity and physical function upon performance
testing. These impairments, in addition to cognitive function and mental health, lead to
significant reductions in quality of life for these survivors.
While viral reservoirs, systemic and organ-level inflammation are leading hypotheses for
the mechanistic underpinnings of LC, no trials to date have investigated the use of
agents targeting these mechanisms. Similar chronic inflammation plays a crucial role in
the increased risk of cardiovascular disease (CVD) and NCI for people with HIV (PWH) as
indicated by elevated soluble and cellular markers of inflammation, endothelial
dysfunction, and hypercoagulability in this population. Activation of the Janus kinase
(JAK)-STAT pathway, which drives a proinflammatory milieu, has been reported during HIV
infection and is associated with CVD, NCI, and HIV persistence. Even in the absence of a
viral infection, these same conditions and comorbidities are driven by a very similar
chronic inflammatory state.
Drug: Baricitinib
4mg encapsulated, pre-formed tablet PO once daily for 24 weeks.
Other Name: OLUMIANT
Other: Placebo
Encapsulated, pre-formed tablet PO once daily for 24 weeks.
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 that
the participant has been informed of all pertinent aspects of the study and was
willing 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 of
SARS-CoV-2 infection, not known to be attributable to another cause upon assessment
by 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., chest
pain, palpitations, shortness of breath, cough, fainting spells), musculoskeletal
symptoms (e.g., muscle aches, joint pain), gastrointestinal symptoms (e.g., nausea,
diarrhea). Although other symptoms (e.g., skin rash, hair loss, mental health
symptoms, trouble with smell/taste, genitourinary symptoms) will be recorded and
tracked, at least one core symptoms listed above must be present.
b. Symptoms must have started after January 2020 and be present for at least 6
months prior to screening. Symptoms that wax and wane must have been initially
present at least 6 months prior to screening.
c. Symptoms must be reported to have an impact on quality of life and/or everyday
functioning and to be at least somewhat bothersome.
d. Symptoms cannot be explained by an alternative diagnosis. e. Cognitive impairment
present defined by having at least 20% positive items (answered subjectively worse
or much worse) on the 41-item modified ECog questionnaire.
Cohort #2 (n=50):
1. Evidence of personally signed and dated informed consent document indicating that
the participant has been informed of all pertinent aspects of the study and was
willing 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 Epidemiologists
Standardized Surveillance Case Definition for COVID-19): i. At least two of the
following 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, or
difficulty breathing.
-OR- iii. Severe respiratory illness with at least one of the following: clinical or
radiographic 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 of
SARS-CoV-2 infection, not known to be attributable to another cause upon assessment
by 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., chest
pain, palpitations, shortness of breath, cough, fainting spells), musculoskeletal
symptoms (e.g., muscle aches, joint pain), gastrointestinal symptoms (e.g., nausea,
diarrhea). Although other symptoms (e.g., skin rash, hair loss, mental health
symptoms, trouble with smell/taste, genitourinary symptoms) will be recorded and
tracked, at least one core symptoms listed above must be present.
b. Symptoms must have started after January 2020 and be present for at least 6
months prior to screening. Symptoms that wax and wane must have been initially
present at least 6 months prior to screening.
c. Symptoms must be reported to have an impact on quality of life and/or everyday
functioning 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 ECog
questionnaire.
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 not
limited to syphilis, as determined by study clinicians (MD, DO, NP, PA, RN, or
equivalent), which may include a review of participant's history and medical
records.
2. Severe cognitive, physical, or psychological disability preventing participation in
the study, as determined by the investigator.
3. Moderate or High risk of suicidality, as determined by the modified Columbia Suicide
Severity Rating Scale (mC-SSRS).
4. History of a major adverse cardiovascular event (MACE) within the 3 months prior to
enrollment.
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 another
study 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 breastfeed
during the course of the study.
11. Venous thromboembolism in the past 6 months prior to screening or felt to be at
increased 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 the
CKD-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: Individuals
with a positive Hepatitis B core antibody will be excluded even in the presence of a
positive Hepatitis B surface antibody due to the risk of reactivation.
26. Positive for Hepatitis C at the time of Screening. Note: treated or cleared
Hepatitis 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/complicated
herpes zoster or herpes simplex infection (e.g., VZV encephalitis).
28. History of untreated latent tuberculosis infection (diagnosed with QuantiFERON-TB
Gold Plus testing) or active tuberculosis whether treated or untreated. Note: those
with a positive PPD who have a history of BCG vaccine and a negative QuantiFERON-TB
Gold Plus test will remain eligible).
29. History of current or recent (< 30 days from screening) sepsis or clinically
significant viral, bacterial, fungal, or parasitic infection, according to the
determination 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 plasma
RNA viral load > 48 copies/mL within 1 year of study screening, including requiring
the most recent within 3 months of screening. Blips (VL > 48 copies/mL but < 200
copies/mL) are permitted if preceded and followed by values below the assay limit of
quantification.
31. Immunocompromised as defined by NIH COVID-19 guidelines (see Appendix) and, in the
opinion of the investigator, at an unacceptable risk for participating in the study.
32. Treatment with another investigational drug or device as part of an interventional
study within 30 days of study screening.
33. In the opinion of the investigator, unable to reliably follow-up for the duration of
the study and/or are unable to follow study restrictions/procedures.
34. Persons of childbearing potential under age 55 who are unwilling or unable to
abstain from sex or to use at least one acceptable method of contraception from the
time of screening though at least 28 days after the end of the study intervention
period. Note: Acceptable methods include barrier contraceptives (condoms or
diaphragm) with spermicide, intrauterine devices (IUDs), other contraceptives, oral
contraceptive pills, and surgical sterilization. Participants unwilling to be
counseled about risks related to pregnancy or breastfeeding.
35. Participants actively breastfeeding, who are unwilling to stop breastfeeding for the
duration 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.
University of California San Francisco
San Francisco, California, United States
University of Minnesota
Minneapolis, Minnesota, United States
Vanderbilt University Medical
Nashville, Tennessee, United States
Amy E. Bazzoni, BA
615-343-8010
vccrvlcstudy@vumc.org
Wes Ely, M.D.
Wes Ely, M.D., Principal Investigator
Vanderbilt University Medical Center