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

NCT06128967 | Completed Phase 3 DMC

• 1 other identifier: TOGETHER_REVIVE
• Study Type: interventional
• Target: 399
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Chronic Fatigue Syndrome; Long COVID-19 Syndrome

Keywords

Long COVID-19 Syndrome; Fluvoxamine; Metformin; Adaptive Trial Design; Randomized Controlled Trial

Outcome Measures

Primary Outcomes (1)

• Improvement on Fatigue Severity Score Scale (FSS)

  Improvement on Fatigue Severity Score Scale (FSS)

  Day 60 after randomization

Secondary Outcomes (6)

• Improvement on Fatigue Severity Score Scale (FSS)

  Day 30 after randomization

• Improvement on Fatigue Severity Score Scale (FSS)

  Day 30 post Study Drug Termination (Day 90 after randomization)

• Reduction on any cause hospitalization

  Day 60 after randomization

• Safety of metformin

  Since randomization up to Day 60 (last IMP dose)

• Safety of Fluvoxamine

  Since randomization up to Day 60 (last IMP dose)

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Placebo talc pills of same shape, color, weight dispensed in coded bottles. Each bottle contains 120 pills

Drug: Fluvoxamine Maleate 100 MG; Drug: Metformin Extended Release Oral Tablet

Fluvoxamine 100 mg

ACTIVE COMPARATOR

Fluvoxamine maleate 100 mg pills dispensed in coded bottles. Each bottle contains 120 pills

Drug: Placebo

Metformin XR 500 mg

ACTIVE COMPARATOR

Metformin 500 mg Extended release pills dispensed in coded bottles. Each bottle contains 120 pills

Drug: Placebo

Interventions

Fluvoxamine Maleate 100 MG DRUG

Fluvoxamine Maleate 100 mg each pills

Placebo

Placebo DRUG

Placebo talc pills of same shape, color, weight if compared with active comparator

Fluvoxamine 100 mg; Metformin XR 500 mg

Metformin Extended Release Oral Tablet DRUG

Metformin Extended release oral tablets of 750 mg each pill

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;
• 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;

Sponsors & Collaborators

• Cardresearch: lead

Study Sites (6)

CARDRESEARCH - Cardiologia Assistencial e de Pesquisa

Belo Horizonte, Minas Gerais, 30150240, Brazil

Location

City of Brumadinho

Brumadinho, Minas Gerais, 35.460-000, Brazil

Location

Governador Valadares City Public Health Authority

Governador Valadares, Minas Gerais, Brazil

Location

City of Ibirité Public Health Authority

Ibirité, Minas Gerais, Brazil

Location

Sociedade Padrao de Educacao Superior

Montes Claros, Minas Gerais, Brazil

Location

Universidade Federal de Ouro Preto

Ouro Preto, Minas Gerais, 35400000, Brazil

Location

Related Publications (1)

• 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.

  PMID: 41911553 DERIVED

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome; Fatigue Syndrome, Chronic

Interventions

Fluvoxamine

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Muscular Diseases; Musculoskeletal Diseases; Encephalomyelitis; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Oximes; Hydroxylamines; Amines; Organic Chemicals

Study Officials

• Gilmar Reis, MD,PhD.

  Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, adaptive, randomized, double-blind, placebo-controlled, prospective, pharmacological intervention trial

Study Record Dates

• First Submitted: November 10, 2023
• First Posted: November 13, 2023
• Study Start: October 18, 2023
• Primary Completion: July 1, 2025
• Study Completion: August 1, 2025
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: A year after protocol termination
• Access Criteria: To be defined

Locations

BR (6)