Abstract:
Background: Postacute sequelae of SARS-CoV-2, or long COVID, presents a major therapeutic challenge, with fatigue being a prevalent and debilitating symptom.
Objective: To assess the efficacy of fluvoxamine and metformin for long COVID fatigue.
Design: Randomized, placebo-controlled, adaptive trial. (ClinicalTrials.gov: NCT06128967).
Setting: Outpatient sites in Brazil.
Participants: 399 adults with fatigue persisting 90 or more days after confirmed SARS-CoV-2 infection.
Intervention: Participants were randomly assigned to fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or matching placebo for 60 days.
Measurements: The primary outcome was change in Fatigue Severity Scale (FSS) score.
Results: Fluvoxamine showed a significant reduction in fatigue compared with placebo at day 60 (mean difference, -0.43 [95% credible interval {CrI}, -0.80 to -0.07]), with a sustained effect at day 90 (mean difference, -0.58 [CrI, -0.98 to -0.16]). Fluvoxamine also improved quality-of-life scores with high posterior probability. Metformin showed no significant benefit. Adverse events were less frequent with fluvoxamine (20.0%) than with metformin (28.8%) or placebo (29.7%). Grade 3 and higher adverse events were rare across all groups.
Limitations: The 90-day follow-up period limits conclusions about the durability of treatment effects, and the exclusive focus on fatigue as the primary outcome does not address other prevalent long COVID symptoms, leaving fluvoxamine’s broader therapeutic utility uncertain.
Conclusion: Fluvoxamine, but not metformin, may be an effective treatment for reducing fatigue and improving quality of life in patients with long COVID.
Primary funding source: The Latona Foundation.
Source: 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. Epub ahead of print. PMID: 41911553. https://www.acpjournals.org/doi/10.7326/ANNALS-25-03959 (Full text)