Long Covid (LC)-REVITALIZE - A Long Covid Repurposed Drug Study

Long Covid represents a significant public health challenge, yet effective treatments remain elusive due to the disease's heterogeneity, limited clinical data, and inconsistent methodologies. A previous analysis of clinical and proteomic data from 1,028 subjects diagnosed with Long Covid across three continents (The LC-Optimize Study) suggests that certain repurposed medications may offer potential therapeutic benefits.

Drug repurposing is based on the principle that many drugs interact with multiple molecular targets and mechanisms of action, potentially extending their effects beyond their original intended use. This phenomenon arises from the complex nature of biological systems and the interactions between drugs and various cellular components, which our research pipeline is designed to identify.

A key advantage of repurposed drugs is that they already have established safety and toxicity profiles, are approved by regulatory authorities, and can therefore expedite clinical trials with sufficient supporting data and justification.

This is a Phase III, double-blind, placebo-controlled, multi-arm platform study that will enroll participants from Brazil, Canada, Italy, Uganda, Zambia, and the United States. The first phase of the study will enroll approximately 348 participants globally, all of whom must have previously tested positive for SARS-CoV-2 and have been experiencing Long Covid symptoms for three months or more. A second phase will follow, guided by the results of the first phase and determined through an interim analysis. This phase, which will occur after a protocol amendment, may involve continued testing of one or both repurposed drugs, combination treatments with an additional repurposed drug, or the introduction of a completely new repurposed drug.

Inclusion criteria

Eligible participants must meet all the following inclusion criteria:

• Adults ≥ 18 years of age and ≤ 65 years of age
• Previous Covid-19 (SARS-CoV-2 infection) within the past four years, as determined by the site investigator using the following certainty scale (based on available clinical history and/or serologic data):

3 - Confirmed Infection (PCR or n-Capsid Test): Prior positive nasopharyngeal or salivary PCR test for Covid-19 (documented proof and/or verbal confirmation by participant) or has positive nucleocapsid antibodies results.

2 - Probable Infection (Antigen Test): Participant verbally confirms a prior positive rapid antigen test without PCR confirmation.

1 - Possible Infection (Viral Syndrome and Epidemiological Link): Participant verbally confirms experiencing symptoms consistent with Covid-19 infection and has an epidemiological link (i.e., exposure to a confirmed case) without any positive testing.

• Persistent or new symptoms diagnosed as "Long Covid" as defined by the World Health Organization; "the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection (Covid-19), with these symptoms lasting for at least 2 months with no other explanation". This diagnosis may come from a healthcare professional experienced in Long Covid diagnosis, or the site investigator. These symptoms must be present for more days than not and must not have been present prior to the onset of SARS-CoV-2 (Covid-19) infection.

• At the time of screening, participants should be experiencing at least one of the following self-reported symptoms or symptom clusters. Participant has self-reported issues with:

• Fatigue
• Breathing
• Circulation
• Memory, thinking, and/or communication
• Muscles and/or joints

These five symptoms or symptom clusters were selected based on unpublished data from the National Institutes for Health and Care Research (NIHR, United Kingdom) and their alignment with five validated SBQ scales. The selection was driven by their prevalence and their significant impact on quality of life as reported in symptom assessments.

• Participant has the ability and is willing to follow study procedures throughout the study

• Participant can provide informed consent

Exclusion criteria

Participants who have any one or more of the following criteria at the time of enrollment will be excluded:

• Participants who do not meet the criteria outlined above
• Participants who are unable to provide their informed consent
• Participants who are pregnant, lactating, or plan to become pregnant during the time of the study
• Persons of childbearing potential who are unwilling or unable to abstain from sex or to use at least one acceptable method of contraception from the time of screening through at least 30 days after the end of the study intervention period. Acceptable methods include barrier contraceptives (e.g., condoms or diaphragm) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. Participants unwilling to be counseled about the risks related to pregnancy or breastfeeding will also be excluded.
• Male participants must take precautions to avoid impregnating a female while participating in this study. If a male participant's partner can become pregnant, she must use an effective and reliable form of birth control, as listed above, during the study and for 30 days after the male participant's last dose of the investigational product. Additionally, male participants must agree to use a latex condom during sexual activity with partners who could become pregnant.
• eGFR <30 mL/min/1.73m2
• Moderate to severe liver dysfunction, defined as Bilirubin > 1.5 x ULN or AST or ALT > 2 x ULN
• Hemoglobin (Hbg) < 8.0 g/dL
• Absolute neutrophil count (ANC) below 1,000 cells/mm³, confirmed with repeat testing
• Absolute lymphocyte count (ALC) below 500 cells/mm³
• Alkaline phosphatase (ALP) levels equal to or greater than three times the upper limit of normal (ULN)
• Creatine phosphokinase (CPK) levels equal to or greater than three times the ULN
• Platelet count below 100,000 cells/mm³, confirmed with repeat testing
• Platelet count above 500,000 cells/mm³, confirmed with repeat testing
• Total fasting cholesterol levels of 280 mg/dL or higher, confirmed with repeat testing
• Fasting low-density lipoprotein (LDL) levels of 180 mg/dL or higher, confirmed with repeat testing
• A personal or family history of long QT syndrome or an electrocardiogram (ECG) during screening showing a corrected QT interval (QTc) of 500 milliseconds or greater, calculated using Fridericia's formula
• Participants with HIV diagnosis
• Participants with active hepatitis B or C diagnosis. Note: treated or cleared hepatitis C is not exclusionary.
• Active herpes zoster infection (visible skin lesions) within 3 months prior to screening, or any history of disseminated or complicated herpes zoster or herpes simplex infection (e.g., VZV encephalitis)
• Participants with active or latent tuberculosis
• Immunocompromised status, as determined by the investigator, that places the participant at an unacceptable risk for study participation
• Active malignancy or lymphoproliferative disorder that has not been in remission for at least five years. Localized non-melanoma skin cancers that have been definitively treated are not exclusionary.
• Positive SARS-CoV-2 test in the last 30 days or symptomatic with Covid-19 like illness
• Previous admission to an intensive care unit (ICU) for the treatment of acute COVID-19 infection
• Any history of deep venous thrombosis, pulmonary embolism, unstable angina, atrial fibrillation, ventricular fibrillation, or myocardial infarction or stroke
• History of sepsis or a significant viral, bacterial, fungal, or parasitic infection within 30 days prior to enrollment, as determined by the investigator.
• Use of one or more of the study drugs within 30 days prior to enrollment for the original indication or other purposes
• Known allergic reactions to the components of the study drugs
• Any prior exposure to JAK inhibitors
• Taking any of the listed medications on the prohibited medications list in Appendix A
• Intake or planned consumption of any of the following: Taurine, Curcumin, CoQ10, Creatine, Resveratrol, Fisetin, Nicotinamide mononucleotide (NMN), Nicotinamide adenine dinucleotide (NAD+), Quercetin, Glycine, Spermidine, Arginine alpha-ketoglutarate, Ergothioneine, Alpha Lipoic Acid, Carnitine, Benfotiamine, Carnosine, Crocin, N-acetylcysteine
• Covid vaccinations are prohibited within 30 days prior to enrollment
• Live vaccine within the 30 days before enrollment or plan to receive live vaccines during the study period
• Other vaccines, including influenza vaccine, are prohibited within 14 days of enrollment
• Major surgery within 30 days prior to enrollment or plans for major surgery during the study
• Any other co-existing medical condition or concomitant medication/therapy that might in the judgment of the study investigators, potentially impact the participant's safety or ability to adhere to the study protocol or interfere with the meaning of the clinical and research measurements as judged by the study investigators
• Participation in any clinical study within the last 30 days prior to enrollment
• Participants who participated in Phase One of this study (LC-Revitalize) are not eligible to participate in Phase Two
• Currently hospitalized and/or incarcerated