REVERSE-Long COVID-19 With Baricitinib Study (REVERSE-LC)

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)

REVERSE-LC is 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Post-Acute COVID-19 Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Baricitinib 4 MG

Detailed Description

This is a 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 24 weeks (dose adjusted to 2 mg or 1 mg for baseline renal dysfunction) versus the placebo arm for 24 weeks. In addition to safety, a variety of clinical and biological outcome measures will be assessed.

• Study Type: Interventional
• Enrollment (Estimated): 550
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rebecca Abel, MA; Phone Number: 615-875-3763; Email: rebecca.abel@vumc.org
• Study Contact Backup: Name: E. Wesley Ely, MD. MPH; Phone Number: 615-936-2795; Email: wes.ely@vumc.org

Study Locations

• United States
  • California
    • San Francisco, California, United States, 30329
      • University of California San Francisco
      • Contact: Priscilla Hsue, MD; Email: priscilla.hsue@ucsf.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
      • Contact: Vince Marconi, MD; Email: vcmarco@emory.edu
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
      • Contact: Carolyn Bramante; Email: bramanate@umn.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University
    • Nashville, Tennessee, United States, 37232-8300
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

1. Obtain a signed and dated informed consent form from participant
2. State their willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged ≥18 years old

4. Meet the following criteria for "Post-COVID Condition" or Long COVID:

   1. 6-months prior, documented SARS-CoV-2 infection
   2. Cognitive impairment as defined by having at least 20% positive (worse or much worse) items on the ECOG assessment
   3. 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.
5. Ability to take oral medication and be willing to adhere to the baricitinib regimen
6. 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:

1. Pre-existing cognitive impairment not exacerbated by acute COVID as determined by study physicians after thorough review of participant's history and medical records
2. Current use of baricitinib or other disease-modifying antirheumatic drug (DMARDs)
3. Known allergic reactions to components of the baricitinib
4. Have ever been randomized in this study or any other study investigating baricitinib
5. Positive SARS-CoV-2 PCR or rapid Antigen test in the past 14 days
6. Pregnancy or breastfeeding
7. Any history of venous thromboembolism ever
8. History of malignancy or lymphoproliferative disorder
9. Renal dysfunction with estimated glomerular filtration rate of < 30 mL/min/1.73m2
10. Absolute Neutrophil Count (ANC) <1200 cells/mm3
11. History or evidence of severe or end-stage liver disease (e.g. bilirubin ≥1.5x or AST/ALT >2x normal).
12. Positive Hepatitis B surface antibody, antigen or core antibody, or Positive Hepatitis C RNR or antigen
13. Positive HIV 4th generation (antibody/antigen) ELISA test
14. 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
15. History of latent (diagnosed with Quantiferon testing) or active tuberculosis
16. History of a current or recent (< 30 days from screening) clinically significant viral, bacterial, fungal, or parasitic infection
17. History of chronic alcohol abuse, Intravenous (IV) drug abuse, or other illicit drug abuse within the 2 years prior to study entry
18. Are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study
19. Treatment with another investigational drug or other intervention < 30 days of study enrollment
20. Are unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures
21. Severe cognitive, physical, or psychological disability that would prevent participation in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; These participants will receive placebo for 24 weeks (6 mo)	Drug: Placebo; Placebo
Experimental: Intervention #1; These participants will receive baricitinib 4 mg daily for 24 weeks	Drug: Baricitinib 4 MG; Nonproprietary name: Baricitinib; Other Names: Olumiant

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Yale University; Emory University; University of California, San Francisco; Vanderbilt University; University of Minnesota
• Investigators: Principal Investigator: E. Wesley Ely, MD, MPH, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 30, 2029

Study Registration Dates

• First Submitted: March 28, 2023
• First Submitted That Met QC Criteria: May 11, 2023
• First Posted (Actual): May 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome
• Other Study ID Numbers: U13800

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No