As-needed use of budesonide plus formeterol as good as daily use of steroid (SYGMA 2)

Reference

Bateman ED, Reddel HK, O'Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378(20):1877-1887.

Synopsis

This industry-sponsored noninferiority trial included 4215 patients, of whom 4176 had data available for analysis. Their mean age was 41 years, and approximately 50% controlled their asthma by using a daily inhaled glucocorticoid during the previous year; the other half had uncontrolled asthma using a short-acting beta-agonist (SABA) alone. Fully 22% had a severe exacerbation during the previous year, defined as the need for at least 3 days of systemic steroids, hospitalization, or an emergency department visit, which seems high for "mild asthma." As in the similar SYGMA 1 trial published in the same issue of this journal, mild asthma was defined as asthma that is uncontrolled using only a SABA as needed, or well controlled using a low-dose steroid inhaler. After a run-in period during which patients used only an as-needed SABA (terbutaline 0.5 mg), the patients were randomized to receive: (1) placebo inhaler twice daily plus budesonide 200 mcg/formeterol 6 mcg, as needed; or (2) budesonide 200 mcg twice daily plus as-needed use of terbutaline 0.5 mg. This trial was initially designed as a superiority trial to show that one of the interventions was better than the other. However, a lower-than-expected rate of exacerbations and a higher-than-expected rate of adherence to the daily inhaled steroid hurt the power, so the authors moved the goalposts midgame and declared it a noninferiority trial. Noninferiority was defined as no more than a 20% increase in the number of severe exacerbations. Although it's not good research practice to change goals midstream, in some ways this is a more interesting research question, and the noninferiority margin the authors chose seems clinically reasonable. After one year, there was indeed no difference between the groups regarding the likelihood of a severe exacerbation (0.11 for as-needed use and 0.12 for daily steroid inhaler per patient per year). There was also no differences between groups regarding the time to a first severe exacerbation or regarding different types of severe exacerbations (ie, hospitalization or emergency department visit). Adverse events between groups were similar. Not surprisingly, patients in the as-needed inhaler group had only about one-fourth the total steroid dose during the study period.