• Gilmar Reis, Dos Santos Moreira SilvaEduardo AugustoEA0000-0001-5111-9528Research Division, Cardresearch - Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil, and Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Minas Gerais, Brazi, Daniela Carla Medeiros Silva, Lehana Thabane, Vitoria Helena de Souza Campos, Thiago Santiago Ferreira, Castilho Vitor Quirino Dos Santos, Ana Maria Ribeiro Nogueira, Ana Paula Figueiredo Guimaraes Almeida, Cançado Monteiro SavassiLeonardoL0000-0001-6780-0377Public Health, Mental and Family Medicine Department, Ouro Preto Federal University, Minas Gerais, Brazil (L.C.M.S.)., de Figueiredo NetoAdhemar DiasADPublic Health Fellowship Program, Governador Valadares Public Health Authority, Minas Gerais, Brazil (A.D.d.F.N.)., Carina Bitarães, Cruz MilagresAlineAPublic Health, Mental and Family Medicine Department, Ouro Preto Federal University, Minas Gerais, Brazil, and Public Health Care Division, City of Ibirité, Brazil (C.B., A.C.M.)., Eduardo Diniz Callegari, Campos SimplicioMaria IzabelMIResearch Division, Cardresearch - Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil (T.S.F., M.I.C.S., L.B.R., R.O.)., Barra RibeiroLucieneLResearch Division, Cardresearch - Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil (T.S.F., M.I.C.S., L.B.R., R.O.)., Rosemary Oliveira, Ofir Harari, Lindsay A Wilson, Jamie I Forrest, Hinda Ruton, Sheila Sprague, Paula McKay, Christina M Guo, Gordon H Guyatt, Craig R Rayner, David R Boulware, Nicole Ezer, Todd C Lee, Emily Gibson McDonald, Mona Bafadhel, Christopher Butler, Rodrigues SilvaJosueJ0000-0001-7814-2349Platform Life Sciences, Vancouver, British Columbia, Canada (L.A.W., J.I.F., C.M.G., J.R.S.)., Mark Dybul, Edward J Mills, and TOGETHER Investigators.
• ViRx@Stanford, Stanford Biosecurity and Pandemic Preparedness Initiative, Stanford, California; Research Division, Cardresearch - Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil; Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Minas Gerais, Brazil; and Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada (G.R.).
• Ann. Intern. Med. 2023 May 1; 176 (5): 667675667-675.

BackgroundPrevious trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19.ObjectiveTo determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population.DesignRandomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424).Setting12 clinical sites in Brazil.ParticipantsSymptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease.InterventionPatients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos.MeasurementsThe primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions.ResultsRandomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected.LimitationLow event rate overall, consistent with contemporary trials in vaccinated populations.ConclusionTreatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care.Primary Funding SourceLatona Foundation, FastGrants, and Rainwater Charitable Foundation.

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