Clinical trial NCT06128967: A Multicenter, Adaptive, Randomized, doublE-blinded, Placebo-controlled Study in Participants With Long COVID-19: The REVIVE Trial
Official title: An Adaptive, Randomized, doublE-blind, Placebo-controlled, Prospective, Pharmacological interVention Study In Participants With Long COVID-19 Syndrome: REVIVE-TOGETHER Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Long COVID-19 Syndrome
Chronic Fatigue Syndrome
Keywords: Long COVID-19 Syndrome
Fluvoxamine
Metformin
Adaptive Trial Design
Randomized Controlled Trial
Lead sponsor: Cardresearch
Sponsor class: OTHER
First posted: 2023-11-13
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, adaptive, randomized, double-blind, placebo-controlled, prospective, pharmacological intervention trial
Primary purpose: TREATMENT

Brief summary: Date of notification letter to the IRB informing start of recruitment activities: October 21, 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 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Improvement on Fatigue Severity Score Scale (FSS)
timeFrame: Day 60 after randomization
Secondary outcomes:
measure: Improvement on Fatigue Severity Score Scale (FSS)
timeFrame: Day 30 after randomization
measure: Improvement on Fatigue Severity Score Scale (FSS)
timeFrame: Day 30 post Study Drug Termination (Day 90 after randomization)
measure: Reduction on any cause hospitalization
timeFrame: Day 60 after randomization
measure: Safety of metformin
timeFrame: Since randomization up to Day 60 (last IMP dose)
measure: Safety of Fluvoxamine
timeFrame: Since randomization up to Day 60 (last IMP dose)
measure: Death of any cause
timeFrame: Since randomization up to Day 60 (last IMP dose)
Other outcomes:
Locations:
city: Belo Horizonte
country: Brazil
facility: CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
state: Minas Gerais
city: Brumadinho
country: Brazil
facility: City of Brumadinho
state: Minas Gerais
city: Governador Valadares
country: Brazil
facility: Governador Valadares City Public Health Authority
state: Minas Gerais
city: Ibirité
country: Brazil
facility: City of Ibirité Public Health Authority
state: Minas Gerais
city: Montes Claros
country: Brazil
facility: Sociedade Padrao de Educacao Superior
state: Minas Gerais
city: Ouro Preto
country: Brazil
facility: Universidade Federal de Ouro Preto
state: Minas Gerais
Study officials:
affiliation: Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
name: Gilmar Reis, MD,PhD.
role: STUDY_CHAIR
References: