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.
| Discipline Area | Score |
|---|---|
| Infectious Disease |  |
| Public Health |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
Well designed and executed clinical trial demonstrating clinically significant benefits of fluvoxamine in patients with long COVID who are experiencing fatigue. Given the paucity of evidence for beneficial treatments in this population, this is important evidence.
Well-done trial showing the benefit of metformin for treating fatigue in long COVID.
The authors state: "Given the association of depression with fatigue, we should note that patients with a diagnosis of major depressive disorder or those taking antidepressant medications were excluded from this trial. However, participants with depressive symptoms (in the absence of a formal major depressive disorder diagnosis) were not excluded, reflecting the real-world comorbidity of mood symptoms in long COVID." The authors used EQ-5D-5L which measures health-related quality of life, usual activities, pain/discomfort and anxiety/depression. But they did not separately analyse the depression component, which could explain much of the improvement. Patients with depression often precede clinically diagnosed depression with a long subclinical course. If the patients are depressed this should have been discussed with them and counselling offered. The roots of the depression could lie much earlier (e.g., in childhood).