IRB approval date 14-APR-2024 and public at https://plataformabrasil.saude.gov.br/login.jsf since IURB approval

Long COVID is a multi-systemic condition comprising often severe and persistent symptoms (longer than 12 weeks) that follow a known episode of COVID-19 and cannot be explained by another medical condition. This condition is observed in up to 15% of all individuals after an acute episode of COVID-19, even in those who had a mild and oligosymptomatic SARS-CoV-2 infection. Around 40% of these patients present symptoms that significantly compromise their daily activities.

There is increasing evidence that LONG COVID is accompanied by dysregulated, persistent and uncontrolled inflammation, often accompanied by the development of an autoreactive immune response, including autoantibodies. Symptoms can last months or years, particularly in cases of chronic fatigue syndrome, with significant proportions of individuals having significant chronic impairment, preventing the performance of work and social activities.

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:

1. Age 18 years or older at the time of screening.
2. Willing and able to provide written informed consent, or with a legal representative who can provide informed consent (where approved locally and nationally).
3. 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).
4. 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)
5. Last COVID-19 episode within 24 months of screening.
6. Not currently hospitalized or requiring hospitalization, or having been hospitalized in an intensive care center at the time of the COVID-19 episode.

6. Participants with the following vital data:

1. Heart Rate between 55 and 100 bpm;

2. Temperature below 38o C;

3. 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.

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

   9. Willingness to follow all study procedures.

Exclusion Criteria:

1. Known acute SARS-CoV-2 infection;

2. Inability to understand the content of the Informed Consent Form or to follow the study procedures;

3. Known previous diagnosis of malignant encephalomyelitis/chronic fatigue syndrome, unrelated to SARS-CoV-2 infection;

4. Known pre-existing dysautonomia, unrelated to SARS-CoV-2 infection;

5. Diabetes mellitus (exclusion criteria for the Metformin and Metformin Placebo arm);

6. Known Creatinin Clearance < 30 ml/ min or under chronic renal replacement therapy;

7. Known stroke within 3 months prior to screening;

8. Known severe anemia, defined as < 8 g/dl;

9. Body Mass Index (BMI) > 40.

10. Known diagnosis of Lyme disease;

11. Any use of illicit drugs not related to marijuana within 30 days prior to informed consent;

12. 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;

13. Breastfeeding women;

14. Expected hospitalization for elective surgical procedures that will ensure hospitalization > 48 hs;

15. Contra-indications for Metformin arm eligibility:

    1. Participant currently on metformin use;
    2. Participants with known creatinine clearance < 30 ml/min, history of KDIGO IV or under renal replacement therapy;

16. Contra-indications for Fluvoxamin arm eligibility:

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

17. 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 ;

18. Clinical history of moderate to severe hepatic impairment or liver cirrhosis with Child-Pugh classification C or greater;

19. Clinical history of severe lung disease with significant limitation of activities;

20. Inability of the participant to give consent or adhere to the procedures proposed in the study;

21. 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);

22. Known hypersensitivity and/or intolerance to Fluvoxamine or Metformin;

23. Any clinical condition which, in the investigator's opinion, may prevent participation in this research.

We are prone to share patient level information data to specific researchers that share the same intention. Data sharing request shall be submitted to a local committee for approval.

A year after protocol termination

To be defined

The production of medication bottles is carried out by a pharmaceutical company, which does not have access to members of the research centers. The pills are similar in shape, color, size and weight and are packaged in identical bottles and coded according to each medication arm, this code being inaccessible to the investigator, the sponsor, the medical care provider and the research participant.

The allocation process follows a random sequential distribution into blocks. The posology of the medications is identical for all arms.