The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID
et al., Annals of Internal Medicine, doi:10.7326/ANNALS-25-03959, NCT06128967, Mar 2026
Metformin for COVID-19
3rd treatment shown to reduce risk in
July 2020, now with p < 0.00000000001 from 110 studies.
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.
No treatment is 100% effective. Protocols
combine treatments.
6,500+ studies for
210+ treatments. c19early.org
|
RCT 399 adults with long COVID fatigue in Brazil showing significant benefit with fluvoxamine but not metformin for reducing fatigue severity. Authors hypothesize that fluvoxamine's σ-1 receptor agonism and immunomodulatory properties may address biological drivers of long COVID fatigue.
Study covers metformin and fluvoxamine.
Reis et al., 31 Mar 2026, Randomized Controlled Trial, placebo-controlled, Brazil, peer-reviewed, median age 44.0, 94 authors, study period 18 October, 2023 - 10 February, 2025, trial NCT06128967 (history).
Abstract:
The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID
AnAdaptive Randomized Trial
Gilmar Reis, MD, PhD; Eduardo Augusto dos Santos Moreira Silva, MD, PhD; Daniela Carla Medeiros Silva, MD, PhD; Lehana Thabane, PhD; Thiago Santiago Ferreira, MD; Luiza Lanna França Reis; Ana Paula Figueiredo Guimaraes Almeida, MD; Marcela Menezes Amaral, MD; Leonardo Cançado Monteiro Savassi, MD, PhD; Vitoria Helena de Souza Campos, MD; Maria Izabel Campos Simplicio, BSc Pharm; Luciene Barra Ribeiro, RN, PhD; Thalyne de Souza Medeiros, BSc; Thais Campos Siqueira, RA; Taynara Silva Vieira, BSc; Nayara Drumond Rausse, BSc; Tereza Cristina Garofolo, BSc; Eliane Carreiro Fagundes Silva, RN; Ofir Harari, PhD; Gennaro D ' Urso, PhD; Jamie I. Forrest, PhD; Jay Park, PhD; Jean B. Nachega, MD, PhD; Christopher Lindsell, PhD; Jeffrey S. Glenn, MD, PhD; Kristian Thorlund, PhD; Mark Dybul, MD; and Edward J. Mills, PhD; for the REVIVE Investigators*
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 ef fi cacy of fl uvoxamine 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 con fi rmed SARS-CoV-2 infection.
Intervention: Participants were randomly assigned to fl uvoxamine (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 signi fi cant 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
P ostacute sequelae of SARS-CoV-2 infection, or long COVID, poses a substantial and ongoing global health burden, affecting millions of people after resolution of acute COVID-19 illness (1, 2). Fatigue is among the most prevalent and debilitating symptoms, often persisting for months and impairing quality of life (3 -6). Despite the increasing recognition of long COVID ' s social and economic effects, therapeutic options remain limited (7 -9).
Current management is largely supportive, relying on multidisciplinary care models focused on symptom relief (10, 11). The underlying mechanisms are multifactorial, involving possible persistent viral antigens, immune dysregulation, endothelial dysfunction, and mitochondrial impairment (12, 13). This complicates therapeutic development and highlights the need for targeted interventions addressing the biological drivers of long COVID (14, 15).
difference, 0.58 [CrI, 0.98 to 0.16]). Fluvoxamine also improved quality-of-life scores with high posterior probability. Metformin showed no signi fi cant bene fi t. Adverse events were less frequent with fl uvoxamine (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 fl uvoxamine's broader therapeutic utility uncertain.
Conclusion: Fluvoxamine, but not metformin, may be an effective treatment for..
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