Date of notification letter to the IRB informing start of recruitment activities: October21, 2023.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 byanother medical condition. This condition is observed in up to 15% of all individualsafter an acute episode of COVID-19, even in those who had a mild and oligosymptomaticSARS-CoV-2 infection. Around 40% of these patients present symptoms that significantlycompromise their daily activities.There is increasing evidence that LONG COVID is accompanied by dysregulated, persistentand uncontrolled inflammation, often accompanied by the development of an autoreactiveimmune response, including autoantibodies. Symptoms can last months or years,particularly in cases of chronic fatigue syndrome, with significant proportions ofindividuals having significant chronic impairment, preventing the performance of work andsocial 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.
Drug: Fluvoxamine Maleate 100 MG
Fluvoxamine Maleate 100 mg each pills
Drug: Placebo
Placebo talc pills of same shape, color, weight if compared with active comparator
Drug: Metformin Extended Release Oral Tablet
Metformin Extended release oral tablets of 750 mg each pill
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. 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 stroke within 3 months prior to screening;
7. Known severe anemia, defined as < 8 g/dl;
8. Body Mass Index (BMI) > 35.
9. Known diagnosis of Lyme disease;
10. Any use of illicit drugs not related to marijuana within 30 days prior to informed
consent;
11. 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;
12. Breastfeeding women;
13. Participants using serotonin reuptake inhibitors (donepezil, fluoxetine,
escitalopran, parorexitin);
14. Participants chronically using any of the medications under evaluation (metformin
and fluvoxamine);
15. 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 ;
16. Clinical history of moderate to severe hepatic impairment or liver cirrhosis with
Child-Pugh classification C or greater;
17. Clinical history of severe lung disease with significant limitation of activities;
18. Inability of the participant to give consent or adhere to the procedures proposed in
the study;
19. Taking medications which are known to cause a known side effect of chronic fatigue;
20. Known hypersensitivity and/or intolerance to Fluvoxamine or Metformin;
21. Any clinical condition which, in the investigator's opinion, may prevent
participation in this research.
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
Belo Horizonte, Minas Gerais, Brazil
City of Brumadinho
Brumadinho, Minas Gerais, Brazil
Governador Valadares City Public Health Authority
Governador Valadares, Minas Gerais, Brazil
City of Ibirité Public Health Authority
Ibirité, Minas Gerais, Brazil
Sociedade Padrao de Educacao Superior
Montes Claros, Minas Gerais, Brazil
Universidade Federal de Ouro Preto
Ouro Preto, Minas Gerais, Brazil
Gilmar Reis, MD, PhD
+553132416574 - 4
greis@cardresearch.org
Maria IC Simplicio, Pharm
+553132416574 - 5
maria.izabel@cardresearch.org
Gilmar Reis, MD,PhD., Study Chair
Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA