Randomized Double-Blind Placebo-Controlled Trial EValuating Baricitinib on PERSistent NEurologic and Cardiopulmonary Symptoms of Long COVID (REVERSE-LC)
Overview
- Phase
- Phase 3
- Intervention
- Baricitinib
- Conditions
- Long COVID
- Sponsor
- Wes Ely
- Enrollment
- 550
- Locations
- 19
- Primary Endpoint
- CNS-Vital Signs Global Cognitive Index
- Status
- Recruiting
- Last Updated
- 10 days ago
Overview
Brief Summary
The overarching goal of this study is to determine if baricitinib, as compared to placebo, 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, in participants with Long COVID.
Detailed Description
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.
Investigators
Wes Ely
Professor, Allergy, Pulmonary, and Critical Care Medicine
Vanderbilt University Medical Center
Eligibility Criteria
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):
- •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.
- •Age ≥18 years old.
- •Documented SARS-CoV-2 infection 6 or more months prior to screening, confirmed with acceptable documentation that includes (at minimum) their name, the date the test was taken (must be after January 2020), and details specifying that the positive test was for SARS-CoV-2 infection.
- •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 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.
Exclusion Criteria
- •An individual who meets any of the following criteria will be excluded from participation in this investigation:
- •Qualifying Long COVID symptoms cannot be explained by an infection-associated chronic condition diagnosed prior to the onset of Long COVID (e.g., ME/CFS or other infection-associated chronic condition).
- •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.
- •Severe cognitive, physical, or psychological disability preventing participation in the study, as determined by the investigator.
- •Moderate or High risk of suicidality, as determined by the modified Columbia Suicide Severity Rating Scale (mC-SSRS).
- •History of a major adverse cardiovascular event (MACE) within the 3 months prior to enrollment.
- •Current use of baricitinib or other disease-modifying antirheumatic drug (DMARDs); however, DMARDs with minimal immunomodulatory effects (hydroxychloroquine, i.e., Plaquenil, steroids used for less than 2 weeks, minocycline), are not exclusionary.
- •Known prior allergic reactions to components of the baricitinib.
- •Previously randomized in this study or in the last 30 days have been in another study investigating baricitinib.
- •Positive SARS-CoV-2 NAAT or rapid Antigen test in the 14 days prior to screening.
Arms & Interventions
Baricitinib
Janus kinase inhibitor
Intervention: Baricitinib
Placebo
Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
CNS-Vital Signs Global Cognitive Index
Time Frame: Month 6
Objective neuropsychological function determined using the CNS-Vital Signs Global Cognitive Index between study arms at 6-months, adjusted for baseline. CNS-Vital Signs Global Cognitive Index subscale is an average score derived from the domain scores or a general assessment of the overall neurocognitive status of the participant. The scores range from less than 70 (very low) to above 110 (above average). A higher score means higher neurocognitive function and higher capacity.
Secondary Outcomes
- Mental health measures including depression, anxiety, and stress using the DASS-21 at 6- and 12-months(Months 6 and 12)
- General participant-reported outcomes using the PROMIS-29 at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- Cognitive participant-reported outcomes using the PROMIS-Cognitive Function-Short Form 8a at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- Objective neuropsychological function domains of executive function, memory, processing speed, and motor speed including the CNS-Vital Signs subscale tests at 6-months.(Month 6)
- Objective neuropsychological function domains of executive function, memory, processing speed, and motor speed including the CNS-Vital Signs subscale tests at 12-months.(Month 12)
- Exercise capacity including the 6-minute walk test (6MWT) at 6- and 12-months(Months 6 and 12)
- Cardiopulmonary exercise testing (CPET)(Months 6 and 12)
- Quality-of-life measures including the EuroQOL-5D-5L at 3-, 6-, and 12-months(Months 3, 6, and 12)
- Post-exertional malaise including the modified De Paul Symptom Questionnaire - Post-Exertional Malaise (mDSQ-PEM) at 6- and 12-months(Months 6 and 12)
- Effect of breathlessness on daily activities including the Modified Medical Research Council Dyspnea Scale (mMRC) at 6- and 12-months(Months 6 and 12)
- Post COVID-19 symptom burden including the Symptom Burden Questionnaire for Long COVID (SBQ-LC) Circulation Subscale at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- Orthostatic intolerance using the Orthostatic Intolerance Questionnaire (OIQ) at 3-, 6-, and 12-months(Months 3, 6, and 12)
- Autonomic dysfunction using the COMPASS-31 at 3-, 6-, and 12-months.(Months 3, 6, and 12)
- Objective neuropsychological function domains of executive function, memory, processing speed, and motor speed including the CNS-Vital Signs subscale tests at 6-months.(Month 6)
- Objective neuropsychological function domains of executive function, memory, processing speed, and motor speed including the CNS-Vital Signs subscale tests at 12-months.(Month 12)
- Modified Everyday Cognition (mECog)(Months 3, 6 and 12)
- Exercise capacity including the 6-minute walk test (6MWT) at 6- and 12-months(Months 6 and 12)
- Cardiopulmonary exercise testing (CPET)(Months 6 and 12)
- Quality-of-life measures including the EuroQOL-5D-5L at 3-, 6-, and 12-months(Months 3, 6, and 12)
- Post-exertional malaise including the modified De Paul Symptom Questionnaire - Post-Exertional Malaise (mDSQ-PEM) at 6- and 12-months(Months 6 and 12)
- Effect of breathlessness on daily activities including the Modified Medical Research Council Dyspnea Scale (mMRC) at 6- and 12-months(Months 6 and 12)
- Post COVID-19 symptom burden including the Symptom Burden Questionnaire for Long COVID (SBQ-LC) Circulation Subscale at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- General participant-reported outcomes using the PROMIS-29 at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- Cognitive participant-reported outcomes using the PROMIS-Cognitive Function-Short Form 8a at 1-, 3-, 6-, and 12-months(Months 1, 3, 6, and 12)
- Mental health measures including depression, anxiety, and stress using the DASS-21 at 6- and 12-months(Months 6 and 12)
- Orthostatic intolerance using the Orthostatic Intolerance Questionnaire (OIQ) at 3-, 6-, and 12-months(Months 3, 6, and 12)
- Autonomic dysfunction using the COMPASS-31 at 3-, 6-, and 12-months.(Months 3, 6, and 12)