The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID: An Adaptive Randomized Trial
In adults with long COVID fatigue, fluvoxamine improved fatigue and quality of life; metformin did not.
*Adaptive randomized placebo-controlled trial; Level 1b (OCEBM).
*Adaptive randomized placebo-controlled trial; Level 1b (OCEBM).
Citation
Reis G, dos Santos Moreira Silva EA, Medeiros Silva DC, et al. The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID: An Adaptive Randomized Trial. Annals of Internal Medicine. 2026;179:621-628. doi:10.7326/ANNALS-25-03959
Background
Long COVID commonly causes persistent, disabling fatigue, and proven drug treatments are limited. This trial tested whether fluvoxamine or metformin reduces fatigue in long COVID.
Patients
399 adults in Brazil with new or worsening fatigue lasting at least 90 days after confirmed (or clinically diagnosed) SARS-CoV-2 infection and a Fatigue Severity Scale score of 4 or higher. Key exclusions included active infection, prior chronic fatigue syndrome, pregnancy/breastfeeding, severe anemia, uncontrolled psychiatric illness or use of certain psychiatric medicines, and current use of metformin (for the metformin comparison).
Intervention
Fluvoxamine 100 mg twice daily for 60 days, or metformin extended-release 750 mg twice daily for 60 days.
Control
Matching placebo.
Outcome
Primary: change in Fatigue Severity Scale score (range 1–7; higher is worse) from baseline to day 60. Secondary: quality of life (EuroQol 5-dimension questionnaire) and “recovery” (Fatigue Severity Scale score under 3).
Follow-up Period
90 days
Results
| Outcome (vs placebo) | Effect |
|---|---|
| Fatigue Severity Scale change at day 60 (primary) | Fluvoxamine: −0.43 points (95% range of likely values, −0.80 to −0.07) |
| Fatigue Severity Scale change at day 90 | Fluvoxamine: −0.58 points (−0.98 to −0.16) |
| Quality of life at day 30 | Fluvoxamine: +0.10 (0.05 to 0.15) |
| Quality of life at day 60 | Fluvoxamine: +0.06 (0.01 to 0.11) |
| Recovery at day 60 (Fatigue Severity Scale under 3) | Fluvoxamine: risk ratio 1.36 (1.08 to 1.71) |
Metformin showed no meaningful benefit on fatigue. Adverse events were reported in 20.0% (fluvoxamine), 28.8% (metformin), and 29.7% (placebo); severe events were rare.
Analyses were intention-to-treat.
Limitations
Follow-up was only 90 days, so long-term benefit is uncertain. The study focused on fatigue, not the full range of long COVID symptoms. The average fatigue improvement was modest on a 1–7 scale. All participants were from Brazil, and early stopping reduced precision (especially for metformin).
Funding
Latona Foundation; funder had no role in the study.
Clinical Application
For long COVID patients with prominent fatigue, consider a monitored 60-day trial of fluvoxamine; do not use metformin solely for fatigue based on this study.
Discussion
Sign in to join the discussion.
In this adaptive randomized, placebo-controlled trial, fluvoxamine reduced Fatigue Severity Scale scores versus placebo at day 60 (mean difference −0.43; 95% CrI −0.80 to −0.07). Is this effect clinically meaningful and practice-changing given self-reported fatigue outcomes, early stopping, and only 90-day follow-up? The study reports a Bayesian 95% credible interval (CrI) for the day-60 fatigue effect of fluvoxamine vs placebo: −0.80 to −0.07. Which interpretation is most accurate?