Fluvoxamine and Inhaled Budesonide: Novel Combination Reduced Incidence of Severe COVID-19

A randomized platform trial of therapies repurposed for COVID-19 has found the combination of fluvoxamine and inhaled budesonide potentially useful, and more likely to prevent progression of early symptoms than either agent alone.

"Our study is, to our knowledge, among the first to evaluate a drug combination for treatment of ambulatory patients with COVID-19 in a randomized trial," indicated principal investigator Edward Mills, PhD, Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada, and colleagues.

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"Our study builds on several previous trials that evaluated each drug independently. The combined effect seems to offer benefits over individual use of each drug," Mills and colleagues reported.

The TOGETHER placebo-controlled platform trial commenced in June, 2020, and has now evaluated 10 drugs for potential repurposing against COVID-19, including hydroxychoroquine, ivermectin and metformin. The current trial with the combination of fluvoxamine and budesonide was conducted at 12 outpatient clinics in Brazil, in collaboration with the report lead author Gilmar Reis, MD, PhD, Research Division, Cardresearch‑Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil.

The effectiveness of the combination in preventing progression of early symptoms of SARS-CoV-2 infection was evaluated in a cohort with a high rate of vaccination (approximately 95%) and individuals with at least 1 risk factor for disease progression. The investigators note that this population is similar to many others in having limited, or no access to antiviral therapeutics.

"Although oral therapeutics for COVID-19 are available in the United States and, to a lesser extent, in other high-income countries, they are predominately prescribed in elderly populations. These drugs are largely unavailable in low- and middle-income countries. For that reason, the use of repurposed drugs may be an important option for health care providers," Mills and colleagues observed.

Trial participants were at least 18 years of age, had presented at clinics within 7 days of experiencing symptoms consistent with COVID-19, were positive on rapid test for SARS-CoV-2 infection; and had at least 1 high-risk criterion for deterioration, such as diabetes mellitus, cardiovascular disease, or obesity.

In addition to usual care, participants were randomly assigned to receive either fluvoxamine and budesonide (n=738) or placebo matching the oral and inhalation dosage forms (n=738). The active treatment regimen was fluvoxamine 100mg twice daily for 10 days and inhaled budesonide 800mcg twice daily for 10 days. The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours or hospitalization for suspected complications of worsening COVID-19.

FINDINGS

The investigators reported that those with active treatment in addition to usual care were less likely to remain in the emergency setting or to be hospitalized for symptoms of COVID-19 than those on usual care with placebo (1.8% [95% CI 1.1-3.0%] compared to 3.7% [2.5-5.3%]).Their relative risk was 0.5 (0.25-0.92) with a probability of superiority of 98.7%.

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

Mills discussed other possible TOGETHER research targets with Contagion. "In terms of combinations, I would like to see Paxlovid with peginterferon Lambda. I suspect it would be the most effective possible combination," he said.

Although the current trial was not designed with long-term follow-up to discern whether the active treatment mitigated development of long COVID (post-acute COVID-19 syndrome, PACS), Mills confirmed that the group is interested in this outcome.

"We are just beginning a long COVID treatment trial and I suspect this combination will be one of our interventions," Mills said. "It seems combination therapies will be key for long COVID."

Reference: Reis G, Silva EASM, Thabane L, et al. Oral fluvoxamine with inhaled budesonide for treatment of early onset COIVD-19. Ann Intern Med.

doi:10.7326/M22-3305

https://www.acpjournals.org/doi/10.7326/M22-3305