A Multicenter, Adaptive, Randomized, doublE-blinded, Placebo-controlled Study in Participants With Long COVID-19: The REVIVE Trial

There is currently no approved therapies for Long COVID. Several clinical trials have been developed to address this clinical condition, however the results were based on small-scale pilot studies. We developed this adaptive, large-scale, prospective, double-blind clinical trial to evaluate the effect of chronic immune-inflammatory modulation on persistent Long-COVID symptoms.

Inclusion criteria

• Age 18 years or older at the time of screening.
• Willing and able to provide written informed consent, or with a legal representative who can provide informed consent (where approved locally and nationally).
• Previous confirmed case of SARS-CoV-2 infection (e.g., reports having a positive nucleic acid amplification test or a professional-use SARS-CoV-2 rapid antigen diagnostic test or positive self-test).
• Participants with a clinical picture compatible with LONG COVID according to international definitions: (www.nice.org.uk/guidance/ng188, https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID -19_condition-Clinical_case_definition-2021.1), and fatigue symptoms with an average score of at least 03 on the Fatigue Analog Scale (FSS)
• Last COVID-19 episode within 24 months of screening.
• Not currently hospitalized or requiring hospitalization, or having been hospitalized in an intensive care center at the time of the COVID-19 episode.

• Participants with the following vital data:

• Heart Rate between 55 and 100 bpm;
• Temperature below 38o C;
• Oxygen saturation ≥ 95%. 7. Patients of childbearing potential or with partners of childbearing potential must agree to use adequate contraception during the study and up to 90 days of follow-up.

• The symptoms of fatigue cannot be attributed to any other cause (in the researcher's opinion).

• Willingness to follow all study procedures.

Exclusion criteria

• Known acute SARS-CoV-2 infection;
• Inability to understand the content of the Informed Consent Form or to follow the study procedures;
• Known previous diagnosis of malignant encephalomyelitis/chronic fatigue syndrome, unrelated to SARS-CoV-2 infection;
• Known pre-existing dysautonomia, unrelated to SARS-CoV-2 infection;
• Diabetes mellitus (exclusion criteria for the Metformin and Metformin Placebo arm);
• Known Creatinin Clearance < 30 ml/ min or under chronic renal replacement therapy;
• Known stroke within 3 months prior to screening;
• Known severe anemia, defined as < 8 g/dl;
• Body Mass Index (BMI) > 40.
• Known diagnosis of Lyme disease;
• Any use of illicit drugs not related to marijuana within 30 days prior to informed consent;
• Pregnant women or women of childbearing age who do not agree to practice an effective method of contraception within 90 days from the date of signing this consent form;
• Breastfeeding women;
• Expected hospitalization for elective surgical procedures that will ensure hospitalization > 48 hs;
• Contra-indications for Metformin arm eligibility:

• Participant currently on metformin use;
• Participants with known creatinine clearance < 30 ml/min, history of KDIGO IV or under renal replacement therapy;
• Contra-indications for Fluvoxamin arm eligibility:

a. Current use of serotonin reuptake inhibitors (donepezil, Fluoxetine, Escitalopran, Paroxetine

• Severe current comorbid psychiatric disorder (e.g., clinical depression, anxiety, sleep disorder, eating disorder, substance abuse), uncontrolled and associated with significant symptoms or requiring the use of a medication contraindicated in this research ;
• Clinical history of moderate to severe hepatic impairment or liver cirrhosis with Child-Pugh classification C or greater;
• Clinical history of severe lung disease with significant limitation of activities;
• Inability of the participant to give consent or adhere to the procedures proposed in the study;
• Taking medications which are known to cause a known side effect of chronic fatigue (except for participants with cardiovascular disease and chronic use of beta-blockers);
• Known hypersensitivity and/or intolerance to Fluvoxamine or Metformin;
• Any clinical condition which, in the investigator's opinion, may prevent participation in this research.