REVERSE-Long COVID-19 With Baricitinib Pilot Study

Study Overview
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Brief Summary
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This is a pilot study for REVERSE-LC, a phase 3 trial of baricitinib versus placebo in adults with neurocognitive impairment (a form of Alzheimer's Disease and Related Dementias or ADRD) or cardiopulmonary symptoms due to Long COVID.

Detailed Description
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This is a pilot study of the multi-site randomized, placebo-controlled, double blind, parallel-design REVERSE-LC phase 3 study. Individuals meeting inclusion criteria will be randomized to one of two arms: the intervention arm of baricitinib 4 mg daily for 12 weeks (dose adjusted to 2 mg or 1 mg for baseline renal dysfunction) versus the placebo arm for 12 weeks. In addition to safety, a variety of clinical and biological outcome measures will be assessed.

Official Title
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REVERSE-Long COVID: A Multicenter Randomized, Placebo-Controlled Clinical Trial of Immunomodulation (With Baricitinib) for Long COVID Related Cognitive Impairment and ADRD (Alzheimer's Disease and Related Dementias)- Pilot Study

Conditions
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Post-Acute COVID-19 Syndrome

Intervention / Treatment
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* Drug: Baricitinib 4 MG


Participation Criteria
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Eligibility Criteria
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In order to be eligible to participate in this study, an individual must meet all of the following criteria: Obtain a signed and dated informed consent form from participant State their willingness to comply with all study procedures and availability for the duration of the study Male or female, aged ≥18 years old Meet the following criteria for Post-COVID Condition or Long COVID: 6-months prior, documented SARS-CoV-2 infection Cognitive impairment as defined by having at least 20% positive (worse or much worse) items on the ECOG assessment Neurocognitive symptoms must have been present for at least 60 days prior to screening. Symptoms that wax and wane must have been initially present at least 60 days prior to screening. Ability to take oral medication and be willing to adhere to the baricitinib regimen Females of childbearing potential must agree to either abstinence or 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), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Pre-existing cognitive impairment not exacerbated by acute COVID as determined by study physicians after thorough review of participant's history and medical records Current use of baricitinib or other disease-modifying antirheumatic drug (DMARDs) Known allergic reactions to components of the baricitinib Have ever been randomized in this study or any other study investigating baricitinib Positive SARS-CoV-2 PCR or rapid Antigen test in the past 14 days Pregnancy or breastfeeding Any history of venous thromboembolism ever History of malignancy or lymphoproliferative disorder Renal dysfunction with estimated glomerular filtration rate of < 30 mL/min/1.73m2 Absolute Neutrophil Count (ANC) <1200 cells/mm3 History or evidence of severe or end-stage liver disease (e.g. bilirubin ≥1.5x or AST/ALT >2x normal). Positive Hepatitis B surface antibody, antigen or core antibody, or Positive Hepatitis C RNR or antigen Positive HIV 4th generation (antibody/antigen) ELISA test Have had symptomatic herpes zoster infection within 3 months prior to study entry or have a history of disseminated/complicated herpes zoster or herpes simplex infection History of latent (diagnosed with Quantiferon testing) or active tuberculosis History of a current or recent (< 30 days from screening) clinically significant viral, bacterial, fungal, or parasitic infection History of chronic alcohol abuse, Intravenous (IV) drug abuse, or other illicit drug abuse within the 2 years prior to study entry Are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study Treatment with another investigational drug or other intervention < 30 days of study enrollment Are unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures Severe cognitive, physical, or psychological disability that would prevent participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, double-blind, parallel-design superiority design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>These participants will receive placebo for 12 weeks (3 mo) | Drug: Baricitinib 4 MG<br>* Nonproprietary name: Baricitinib<br>* Other names: Olumiant;|
| Experimental: Intervention #1<br>These participants will receive baricitinib 4 mg daily for 12 weeks | Drug: Baricitinib 4 MG<br>* Nonproprietary name: Baricitinib<br>* Other names: Olumiant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Enrollment | 2 participants per month, on average, are randomized | 6 months | 
| Diversity in enrollment | 40% of participants will be from individuals disproportionally affected by COVID (Black, Hispanic, Asian, American Indian) | 6 months | 
| Study drug prescribed | 80% of participants received every prescribed dose of the study drug | 9 months | 
| Study withdrawals | Less than 20% participants will be deemed lost to follow up | 18 months | 
| Adverse event reporting | 100% of Serious Adverse Events reported to Data Safety Monitoring Board within 24 hours of study team awareness | 18 months | 
| Study dosing | 100% adherence to study drug dose adjustments guidelines | 9 months | 
| Study completion | 80% of participants adhere to all study procedures and requirements | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe and Serious Adverse Events | Compare the percentage of severe and serious adverse events between study arms from baseline to week 12. | 9 months | 
| Premature study discontinuation | Compare the rate of study drug/placebo premature discontinuation by study arm (tolerability) | 9 months | 
| Global Neuropsychological Function | Assess percentage changes of global neuropsychological function as measured using the CNS Vital Signs Neurocognition Index cognitive battery between baricitinib and placebo study arm from baseline to week 12. | 9 months | 
| Cardiopulmonary testing | Assess percentage changes of exercise capacity (peak VO2) using cardiopulmonary exercise testing (CPET) in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Everyday Cognition | Assess percentage changes of cognitive impairment using Everyday Cognition (ECog) scale in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Functional Status | Assess percentage changes of functional status measures in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Quality of Life Measures | Assess percentage changes of quality of life measures in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Post-Exertional Malaise | Assess percentage changes of post-exertional malaise using De Paul Symptom Questionnaire - Post-Exertional Malaise (DSQ-PEM) in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Shortness of Breath | Assess percentage changes of the effect of breathlessness on daily activities using the Modified Medical Research Council Dyspnea Scale (mMRC) in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Symptom Burden | Assess percentage changes of post COVID-19 symptom burden using the Symptom Burden Questionnaire for Long COVID (SBQ-LC) Circulation Subscale in the baricitinib arm compared to the placebo arm from baseline to week 12 | 9 months | 
| Inflammation biomarkers | Decreases in plasma biomarkers of inflammation in the baricitinib arm compared to placebo arm from baseline to week 12 | 9 months | 
| Viral Reservoirs | Decreases in viral reservoirs for the baricitinib arm compared to placebo arm from baseline to week 12 | 9 months |