Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial
In brief
Fluvoxamine lowered long COVID fatigue scores by 0.58 points at 90 days
In a randomized trial of 399 adults, 60 days of fluvoxamine was associated with a 0.58-point lower average Fatigue Severity Scale score than placebo at day 90, with quality-of-life scores also favoring the drug. Metformin results were inconclusive after dose changes and early stopping; whether fluvoxamine's benefit lasts beyond 90 days remains unknown.
- Journal
- Annals of internal medicine (Q1)
- Published
- 6 October 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Thiago Santiago Ferreira, Luiza Lanna França Reis, et al.
- PMID
- 42832803
- DOI
- 10.7326/ANNALS-26-02144
Why clinicians should know about it
- Picked for Internal Medicine (top studies of the week, 11 October 2026): Fluvoxamine reduced fatigue severity scale by –0.43 at day 60
Abstract
BACKGROUND: Postacute sequelae of SARS-CoV-2 infection (long COVID) presents a therapeutic challenge, with fatigue being a common, debilitating symptom. OBJECTIVE: To assess the efficacy of fluvoxamine and metformin to treat long COVID fatigue. DESIGN: Randomized, placebo-controlled, adaptive trial. (ClinicalTrials.gov: NCT06128967). SETTING: Outpatient sites in Brazil. PARTICIPANTS: 399 adults with fatigue 90 days to 24 months after confirmed SARS-CoV-2 infection. INTERVENTION: Participants were randomly assigned to fluvoxamine (100 mg twice daily [BID]), extended-release metformin (750 mg BID [n = 71] from October 2023 to April 2024; reduced to 500 mg BID [n = 40] in May 2024 after a protocol amendment until the group was stopped for futility in September 2024), or a matching placebo, each for 60 days with follow-up to day 90. MEASUREMENTS: Change in Fatigue Severity Scale (FSS) score. RESULTS: Median baseline FSS scores ranged from 5.6 to 5.9 across all study groups. The treatment effect on FSS score for fluvoxamine versus placebo showed a mean difference of -0.43 at day 60 and -0.58 at day 90; both had a posterior probability of superiority of 99%. Fluvoxamine also improved quality-of-life scores with a high posterior probability of superiority. Findings for metformin were inconclusive. Incidence of adverse events was lower for fluvoxamine (24.0%) than for metformin, 750 mg BID (45.1%); metformin, 500 mg BID (42.5%); and placebo (35.5%). Grade 3 or higher adverse events were rare (≤2.7%), with no treatment-related deaths. LIMITATIONS: The results were inconclusive for metformin because of a dose change recommended by the data safety and monitoring committee due to adverse effects causing study withdrawal and early termination. The benefit of fluvoxamine after 90 days is unknown. The trial did not address other long COVID symptoms. CONCLUSION: Fluvoxamine shows potential for improving long COVID-associated fatigue and quality of life. PRIMARY FUNDING SOURCE: The Latona Foundation.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.