Jamie I. Forrest PhD, MPH
Scientific Director, Health Equity & Resilience Observatory (HERO)
Faculty of Applied Science
University of British Columbia
Keywords
Long COVID, Fluvoxamine, Metformin, Fatigue, Brazil .
Key Points
Globally, millions are affected by the symptoms of Long COVID including fatigue. Multifactorial mechanisms complicate therapeutic development of pharmacological interventions.
REVIVE-TOGETHER is a 22 site study conducted in Brazil from October 2023 to February 2025 investigating fluvoxamine and metformin for the treatment of Long COVID.
Patients taking fluvoxamine showed a statistically significant reduction in fatigue severity scale and sustained benefits across all endpoints. Metformin results were not statistically significant.
The study explored whether reduced fatigue seen on fluvoxamine is simply due to the drug’s antidepressant effect. The REVIVE-TOGETHER data suggest that the effect is not explained solely by antidepressant activity.
Discussion Themes
Trial procedures differ in Brazil compared with typical trial procedures in North America. Recruitment was handled through Brazil’s public health authority groups. This decentralized system allowed for recruitment of more patients than would have been possible via the typical recruitment methods in North America.
The REVIVE-TOGETHER trial used a previously reported measure of fatigue reduction to determine what was considered a clinically meaningful reduction in fatigue.
Carolyn Bramante, MD, MPH
Division of General Internal Medicine
Departments of Internal Medicine and Pediatrics
Core faculty in the Program in Health Disparities Research and the Center for Pediatric Obesity Medicine
University of Minnesota Medical School
Thomas Murray, PhD
Division of Biostatistics
Coordinating Centers for Biometric Research
University of Minnesota School of Public Health
Keywords
COVID-19; Long COVID; COVID-OUT; Metformin; Ivermectin; Fluvoxamine
Key Points
The COVID-OUT Trial was a multi-arm remotely delivered, de-centralized Phase III clinical trial conducted at 6 institutions including 1431 patients with overweight or obesity, designed to test distinct treatment of COVID-19 with Metformin, Fluvoxamine, and Ivermectin. Arms of the trial included 6 groups: (1) metformin and fluvoxamine, (2) metformin and ivermectin, (3) metformin and placebo, (4) placebo and fluvoxamine, (5) placebo and ivermectin, (6) placebo and placebo.
The primary outcome was a binary, 4-part composite outcome of occurrence of severe COVID-19, defined as hypoxia, emergency department visit, hospitalization, or death. Patients were followed for 10 months after enrollment.
Long COVID was determined by patient-report of clinician-diagnosed Long COVID.
Data on Metformin plus placebo show an absolute risk reduction of 4.4% for Long COVID diagnosis at 300 days. There was a consistent direction of effect of Metformin across subgroups and no evidence of heterogeneity of treatment effect.
Diabetes may be a risk factor for severe COVID-19. New observational and preclinical data from patients with prediabetes and PCOS suggest there may be a dose dependent effect of metformin against SARS-CoV-2.
Metformin is safe, well tolerated, and familiar to providers.
Some limitations of the study include lack of diversity in patient population, methods of ascertainment of Long COVID that may under- or over-ascertain Long COVID, internal validity of oxygen data, and self-report of medication adherence.
Only 3.8% of people in the study who said they had Long COVID received treatment for Long COVID. The COVID-OUT trial data don’t suggest that Metformin will treat Long COVID in someone who already has Long COVID, but there are mechanisms that suggest it may be worth investigating.
Discussion Themes
– We did internally look at an unadjusted comparison of vaccinated vs unvaccinated participants, but this comparison is confounded and not the focus of this work. In the future we will do a full observational analysis predicting Long COVID using these subgroups..
– Earlier treatment versus later treatment with Metformin seems to benefit patients..
– There may be other medications in the space of diabetes that may have anti-inflammatory mechanisms that could be relevant to COVID-19 treatment. GLP-1 receptor agonists may have anti-inflammatory and immune modulatory effects. Also, DPP-4 inhibitors also have some beneficial anti-inflammatory effects. These medications are more expensive and may have a more difficult method of delivery, but could be studied to determine their effect on COVID-19.
