Annals of Internal MedicineThe Effect of Fluvoxamine and Metformin for Fatigue in Patients with Long COVID

⚠️ Small Study / Early Comparative Evidence

The REVIVE-TOGETHER trial randomized 399 adults at outpatient sites in Brazil to 60 days of fluvoxamine, extended-release metformin, or placebo. Participants had fatigue persisting 90 days to 24 months after SARS-CoV-2 infection. Fluvoxamine reduced Fatigue Severity Scale scores relative to placebo at days 60 and 90, while metformin crossed a prespecified futility boundary. The findings provide an early randomized treatment signal, but durability beyond 90 days and generalizability outside the enrolled population remain uncertain.

Clinical Considerations

• Fluvoxamine produced mean treatment effects of −0.43 points at day 60 and −0.58 at day 90, each with a 99% or greater posterior probability of superiority.
• Quality-of-life scores also favored fluvoxamine, with treatment effects of 0.06 at day 60 and 0.07 at day 90.
• Recovery, defined as an FSS score below 3, was more frequent with fluvoxamine at both assessment points.
• The trial assessed fatigue rather than the broader long COVID syndrome and did not establish modification of underlying disease mechanisms.
• Metformin results were inconclusive after gastrointestinal intolerance prompted a dose reduction and the treatment group subsequently stopped for futility.
• The article is a republication following retraction, requiring use of the corrected version and careful verification of any derivative coverage.

Practice Applications

• Interpret fluvoxamine as an early randomized signal rather than an established standard treatment for long COVID fatigue.
• Review the modest absolute FSS difference when discussing the potential clinical importance of the reported benefit.
• Recognize that efficacy beyond 90 days, effects on other long COVID manifestations, and applicability outside Brazil remain unknown.
• Avoid extrapolating metformin evidence from prevention during acute COVID to treatment of established long COVID fatigue.
• Verify that clinical summaries and citations refer to the republished article rather than the retracted version.