'Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19' (Reis et al.); we have said this day one (McCullough, Risch, Ladapo, Zelenko, Alexander, Tenenbaum et al.) that it is

SIGNALS of benefit, no 'one drug', but multi-drug sequenced that is the key in higher risk patients with acute COVID-19 (as well as in other respiratory viruses); safe, tolerable, cheap, available

• Gilmar Reis, Eduardo Augusto dos Santos Moreira Silva, Daniela Carla Medeiros Silva, et al; TOGETHER Investigators. Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19: A Randomized Platform Trial. Ann Intern Med. [Epub 18 April 2023]. DOI: https://doi.org/10.7326/M22-3305, https://www.acpjournals.org/doi/10.7326/M22-3305

This high quality clinical trial in Brazil showed us that a simultaneous administration of combined oral fluvoxamine as well as inhaled budesonide worked to reduce the rate of progression (sequelae) to severe COVID-19 and thus the subsequent requirement for advanced medical care within this high-risk population.

No one drug and we NEVER ever stated that for early treatment. We always argued that until the definitive, declarative, large sample sized, long duration, proper powered with the right patient important outcomes studies were done, that it was imperative that doctors do not sit on their hands as their patients died (as they did) and that they use their clinical discretion and power to prescribe cheap effective combined and sequenced overlapping antivirals, steroids, anti-coagulants etc.

‘Design:

Randomized, placebo-controlled, adaptive platform trial.

Setting:

12 clinical sites in Brazil.

Participants:

Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease.

Intervention:

Patients 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.

Measurements:

The 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.

Results:

Randomization 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.

Limitation:

Low event rate overall, consistent with contemporary trials in vaccinated populations.

Conclusion:

Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care.’