Long COVID-19 SyndromePhase 3REVIVENCT06128967
A Multicenter, Adaptive, Randomized, doublE-blinded, Placebo-controlled Study in Participants With Long COVID-19: The REVIVE Trial
A Phase 3 study testing Fluvoxamine Maleate 100 MG and Metformin Extended Release Oral Tablet in people with Long COVID-19 Syndrome and Chronic Fatigue Syndrome, run by Cardresearch at 6 sites in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Long COVID-19 Syndrome, Chronic Fatigue Syndrome
- What is being tested?
- Fluvoxamine Maleate 100 MG and Metformin Extended Release Oral Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 399 participants
- Where
- 6 sitesBrazil
- Study dates
- 18 Oct 2023to 1 Aug 2025
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 6. 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.
- 8. The symptoms of fatigue cannot be attributed to any other cause (in the researcher's opinion).
- 9. Willingness to follow all study procedures.
Who cannot join
- 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;
- Diabetes mellitus (exclusion criteria for the Metformin and Metformin Placebo arm);
- Known Creatinin Clearance < 30 ml/ min or under chronic renal replacement therapy;
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- 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;
- Participants with known creatinine clearance < 30 ml/min, history of KDIGO IV or under renal replacement therapy;
- Contra-indications for Fluvoxamin arm eligibility:
- Current use of serotonin reuptake inhibitors (donepezil, Fluoxetine, Escitalopran, Paroxetine
- 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 ;
- Clinical history of moderate to severe hepatic impairment or liver cirrhosis with Child-Pugh classification C or greater;
- Clinical history of severe lung disease with significant limitation of activities;
- Inability of the participant to give consent or adhere to the procedures proposed in the study;
- 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);
- Known hypersensitivity and/or intolerance to Fluvoxamine or Metformin;
- Any clinical condition which, in the investigator's opinion, may prevent participation in this research.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Brazil6 sites
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
Belo Horizonte, Minas Gerais, 30150240
City of Brumadinho
Brumadinho, Minas Gerais, 35.460-000
Governador Valadares City Public Health Authority
Governador Valadares, Minas Gerais
City of Ibirité Public Health Authority
Ibirité, Minas Gerais
Sociedade Padrao de Educacao Superior
Montes Claros, Minas Gerais
Universidade Federal de Ouro Preto
Ouro Preto, Minas Gerais, 35400000
About this study
Official title: 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.
Read the 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.
- Conditions
- Long COVID-19 Syndrome, Chronic Fatigue Syndrome
- Being tested
- Fluvoxamine Maleate 100 MG, Placebo, Metformin Extended Release Oral Tablet
- Keywords
- Long COVID-19 Syndrome, Fluvoxamine, Metformin, Adaptive Trial Design, Randomized Controlled Trial
- Medical subject headings
- Post-Acute COVID-19 Syndrome, Fatigue Syndrome, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fluvoxamine Maleate 100 MGDrug
Fluvoxamine Maleate 100 mg each pills
PlaceboDrug
Placebo talc pills of same shape, color, weight if compared with active comparator
Metformin Extended Release Oral TabletDrug
Metformin Extended release oral tablets of 750 mg each pill
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Placebo talc pills of same shape, color, weight dispensed in coded bottles. Each bottle contains 120 pills Receives: 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 Receives: Drug: Placebo |
| Metformin XR 500 mg | Active comparator | Metformin 500 mg Extended release pills dispensed in coded bottles. Each bottle contains 120 pills Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement on Fatigue Severity Score Scale (FSS)
Improvement on Fatigue Severity Score Scale (FSS)
Measured: Day 60 after randomization
Secondary outcomes (6)
Improvement on Fatigue Severity Score Scale (FSS)
Improvement on Fatigue Severity Score Scale (FSS)
Measured: Day 30 after randomization
Improvement on Fatigue Severity Score Scale (FSS)
Improvement on Fatigue Severity Score Scale (FSS)
Measured: Day 30 post Study Drug Termination (Day 90 after randomization)
Reduction on any cause hospitalization
Reduction on any cause hospitalization
Measured: Day 60 after randomization
Safety of metformin
Safety of metformin (intention to treat analysis)
Measured: Since randomization up to Day 60 (last IMP dose)
Safety of Fluvoxamine
Safety of Fluvoxamine (intention to treat analysis)
Measured: Since randomization up to Day 60 (last IMP dose)
Death of any cause
Occurrence of Death of any cause
Measured: Since randomization up to Day 60 (last IMP dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Nov 2023
- Study start18 Oct 2023
- Primary completion1 Jul 2025
- Study completion1 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Long COVID-19 SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Multicenter, adaptive, randomized, double-blind, placebo-controlled, prospective, pharmacological intervention trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 399 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cardresearch
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Gilmar Reis, MD,PhD., Study chair, Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06128967
- Sponsor's protocol ID
- TOGETHER_REVIVE
- Acronym
- REVIVE
- Status last verified
- Apr 2026
- First submitted
- 10 Nov 2023
- Last updated
- 13 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Santiago Ferreira T, 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. Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial. Ann Intern Med. 2026 Oct 6. doi: 10.7326/ANNALS-26-02144. Online ahead of print.
PubMed 42832803Reis 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 May;179(5):621-628. doi: 10.7326/ANNALS-25-03959. Epub 2026 Mar 31.
PubMed 41911553
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Adaptive, Randomized, doublE-blind, Placebo-controlled, Prospective, Pharmacological interVention Study In Participants With Long COVID-19 Syndrome: REVIVE-TOGETHER Trial
- ClinicalTrials.gov ID
- NCT06128967
- Acronym / sponsor ID
- REVIVE / TOGETHER_REVIVE
- Conditions
- Long COVID-19 Syndrome, Chronic Fatigue Syndrome
- Keywords
- Long COVID-19 Syndrome, Fluvoxamine, Metformin, Adaptive Trial Design, Randomized Controlled Trial
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 399 participants (actual)
- Lead sponsor
- CardresearchUniversity, hospital or other
- Study start
- 18 Oct 2023 (actual)
- Primary completion
- 1 Jul 2025 (actual)
- Study completion
- 1 Aug 2025 (actual)
- First posted
- 13 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Multicenter, adaptive, randomized, double-blind, placebo-controlled, prospective, pharmacological intervention trial
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Fluvoxamine Maleate 100 MG, Drug: Metformin Extended Release Oral TabletPlacebo talc pills of same shape, color, weight dispensed in coded bottles. Each bottle contains 120 pills |
| Fluvoxamine 100 mg | Active comparator | Drug: PlaceboFluvoxamine maleate 100 mg pills dispensed in coded bottles. Each bottle contains 120 pills |
| Metformin XR 500 mg | Active comparator | Drug: PlaceboMetformin 500 mg Extended release pills dispensed in coded bottles. Each bottle contains 120 pills |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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.
Key exclusion criteria (26 listed)
- 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;
- Diabetes mellitus (exclusion criteria for the Metformin and Metformin Placebo arm);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fluvoxamine Maleate 100 MGFluvoxamine Maleate 100 mg each pills | Drug | Placebo |
| PlaceboPlacebo talc pills of same shape, color, weight if compared with active comparator | Drug | Fluvoxamine 100 mg, Metformin XR 500 mg |
| Metformin Extended Release Oral TabletMetformin Extended release oral tablets of 750 mg each pill | Drug | Placebo |
Primary outcome
Improvement on Fatigue Severity Score Scale (FSS)
Time frame: Day 60 after randomization
Improvement on Fatigue Severity Score Scale (FSS)
6 secondary outcomes
Improvement on Fatigue Severity Score Scale (FSS)
Time frame: Day 30 after randomization
Improvement on Fatigue Severity Score Scale (FSS)
Time frame: Day 30 post Study Drug Termination (Day 90 after randomization)
Reduction on any cause hospitalization
Time frame: Day 60 after randomization
Safety of metformin
Time frame: Since randomization up to Day 60 (last IMP dose)
Safety of Fluvoxamine
Time frame: Since randomization up to Day 60 (last IMP dose)
Death of any cause
Time frame: Since randomization up to Day 60 (last IMP dose)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2026.
- Derived from this study: PubMed 42832803Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Santiago Ferreira T, 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. Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial. Ann Intern Med. 2026 Oct 6. doi: 10.7326/ANNALS-26-02144. Online ahead of print.
- Derived from this study: PubMed 41911553Reis 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 May;179(5):621-628. doi: 10.7326/ANNALS-25-03959. Epub 2026 Mar 31.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gilmar Reis, MD,PhD. study chair
Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Fluvoxamine Maleate 100 MG and Metformin Extended Release Oral Tablet in people with Long COVID-19 Syndrome and Chronic Fatigue Syndrome, run by Cardresearch at 6 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement on Fatigue Severity Score Scale (FSS) (time frame: Day 60 after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06128967, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2026.