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

An Adaptive, Randomized, doublE-blind, Placebo-controlled, Prospective, Pharmacological interVention Study In Participants With Long COVID-19 Syndrome: REVIVE-TOGETHER Trial

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.

Study Overview

• Status: Completed
• Conditions: Chronic Fatigue Syndrome; Long COVID-19 Syndrome
• Intervention / Treatment: Drug: Fluvoxamine Maleate 100 MG; Drug: Metformin Extended Release Oral Tablet; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 399
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150240
      • CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
    • Brumadinho, Minas Gerais, Brazil, 35.460-000
      • City of Brumadinho
    • Governador Valadares, Minas Gerais, Brazil
      • Governador Valadares City Public Health Authority
    • Ibirité, Minas Gerais, Brazil
      • City of Ibirité Public Health Authority
    • Montes Claros, Minas Gerais, Brazil
      • Sociedade Padrao de Educacao Superior
    • Ouro Preto, Minas Gerais, Brazil, 35400000
      • Universidade Federal de Ouro Preto

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo talc pills of same shape, color, weight dispensed in coded bottles. Each bottle contains 120 pills	Drug: Fluvoxamine Maleate 100 MG; Fluvoxamine Maleate 100 mg each pills; Drug: Metformin Extended Release Oral Tablet; Metformin Extended release oral tablets of 750 mg each pill
Active Comparator: Fluvoxamine 100 mg; Fluvoxamine maleate 100 mg pills dispensed in coded bottles. Each bottle contains 120 pills	Drug: Placebo; Placebo talc pills of same shape, color, weight if compared with active comparator
Active Comparator: Metformin XR 500 mg; Metformin 500 mg Extended release pills dispensed in coded bottles. Each bottle contains 120 pills	Drug: Placebo; Placebo talc pills of same shape, color, weight if compared with active comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement on Fatigue Severity Score Scale (FSS)	Improvement on Fatigue Severity Score Scale (FSS)	Day 60 after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement on Fatigue Severity Score Scale (FSS)	Improvement on Fatigue Severity Score Scale (FSS)	Day 30 after randomization
Improvement on Fatigue Severity Score Scale (FSS)	Improvement on Fatigue Severity Score Scale (FSS)	Day 30 post Study Drug Termination (Day 90 after randomization)
Reduction on any cause hospitalization	Reduction on any cause hospitalization	Day 60 after randomization
Safety of metformin	Safety of metformin (intention to treat analysis)	Since randomization up to Day 60 (last IMP dose)
Safety of Fluvoxamine	Safety of Fluvoxamine (intention to treat analysis)	Since randomization up to Day 60 (last IMP dose)
Death of any cause	Occurrence of Death of any cause	Since randomization up to Day 60 (last IMP dose)

Collaborators and Investigators

• Sponsor: Cardresearch
• Investigators: Study Chair: Gilmar Reis, MD,PhD., Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA

Publications and helpful links

General Publications

• Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Ferreira TS, Reis LLF, Figueiredo Guimaraes Almeida AP, Menezes Amaral M, Savassi LCM, de Souza Campos VH, Campos Simplicio MI, Barra Ribeiro L, de Souza Medeiros T, Campos Siqueira T, Vieira TS, Drumond Rausse N, Garofolo TC, Fagundes Silva EC, Harari O, D'Urso G, Forrest JI, Park J, Nachega JB, Lindsell C, Glenn JS, Thorlund K, Dybul M, Mills EJ; REVIVE Investigators. The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial. Ann Intern Med. 2026 Mar 31. doi: 10.7326/ANNALS-25-03959. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2023
• Primary Completion (Actual): July 1, 2025
• Study Completion (Actual): August 1, 2025

Study Registration Dates

• First Submitted: November 10, 2023
• First Submitted That Met QC Criteria: November 10, 2023
• First Posted (Actual): November 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Metformin; Randomized Controlled Trial; Fluvoxamine; Long COVID-19 Syndrome; Adaptive Trial Design
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Post-Infectious Disorders; COVID-19; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Post-Acute COVID-19 Syndrome; Fatigue Syndrome, Chronic; Organic Chemicals; Amines; Hydroxylamines; Oximes; Fluvoxamine
• Other Study ID Numbers: TOGETHER_REVIVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: A year after protocol termination
• IPD Sharing Access Criteria: To be defined
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No