Two open-label randomized controlled trials (RCTs) on the use of inhaled corticosteroids such as budesonide in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients have helped garner attention towards inhaled corticosteroids as a safe and inexpensive treatment method in non-hospitalized SARS-CoV-2 patients.
The trials - STOIC (Steroids in COVID-19) and PRINCIPLE (Platform Randomized Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) - have shown improved time for recovery in COVID-19 patients and also reduced need for hospitalization or urgent care, with the use of budesonide.
Previous studies have also shown that inhaled medications might have a placebo effect on respiratory symptoms. Two placebo-controlled trials - CONTAIN trial (Inhaled Ciclesonide) and Covis Pharma (industry-sponsored ciclesonide) trial - were conducted recently. Both of them were unsuccessful in proving any benefit in time recovery reduced hospitalizations in COVID-19 patients.
Therefore, to find the overall effect of inhaled corticosteroids on non-hospitalized symptomatic patients of COVID-19, researchers from Canada analyzed all available trial data regarding inhaled corticosteroids. This study is available on the medRxiv* preprint server.
Meta-analysis of 4 randomized controlled trials
The authors used secondary outcome data for complete resolution of symptoms by Day 14, which was conserved for all the four completed inhaled corticosteroid RCTs - STOIC, PRINCIPLE, CONTAIN, and Covis Pharma.
The researchers performed a meta-analysis of all available data from these trials to investigate the outcome of using inhaled corticosteroids as a treatment option in symptomatic outpatients with SARS-CoV-2 infection to inform better clinical practice.
Data from a total of 2,317 subjects from the four trials were obtained and analyzed. The patients from STOIC, CONTAIN and Covis Pharma had an average age of 37 to 45 years, and those from the PRINCIPLE trial had an average age of 64 years.
Symptomatic improvement was greater in open-label trials than in placebo-controlled trials, according to the researchers. The findings suggest that even placebo-controlled trials show a 92.5% probability of any effect and a 78.1% probability of number needed to treat (NNT) ≤50. Consequently, while the open-label studies have shown a high likelihood of reducing hospitalizations, the placebo-controlled trials have only demonstrated modest reductions.
The findings of this meta-analysis favor the use of inhaled corticosteroids such as budesonide or ciclesonide for the resolution of symptoms at day 14 of COVID-19 treatment. The researchers believe that a meta-analysis of individual patients accounting for their age and comorbidities might provide more accurate estimates, especially in subgroups or time to event analysis.
Limitations of the study
According to the authors, a significant limitation of their analysis is the coarseness of available data. Potential bias was also found in urgent care and emergency room utilization because of unblinded providers. Also, the trials were conducted during different waves of COVID-19. Early in the pandemic, more patients might have been referred to the emergency department due to a relative lack of knowledge about the nature of COVID-19 disease progression. The results were also largely influenced by the PRINCIPLE trial, which was conducted in a much older population compared to the other 3 trials.
Identifying effective oral or inhaled medications can be helpful in the early stages of SARS-CoV-2 infection to reduce hospitalization, especially in older patients. More evidence from placebo-controlled trials is needed to minimize bias and for more accurate effect size estimates.
“Overall, there is an ongoing need to identify effective oral or inhaled medications that can be used early in the disease to prevent COVID-19 hospitalization.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.