As-needed use of inhaled glucocorticoids in addition to a fast-acting ß2-agonist (ie, budesonide-formoterol) in patients with mild asthma may be an alternative treatment strategy to more poorly tolerated conventional maintenance therapy, according to results from the Symbicort Given as Needed in Mild Asthma (SYGMA) 1 and SYGMA 2 trials recently published in the New England Journal of Medicine.
“The SYGMA 2 trial was designed in parallel with the SYGMA 1 trial to examine whether, in a more pragmatic study design without daily reminders to use maintenance medication, budesonide-formoterol used as needed would be noninferior to regular budesonide maintenance treatment in preventing severe exacerbations in patients with mild asthma,” wrote the authors of the SYGMA 2 study, led by Eric D. Bateman, MD, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
According to current guidelines, patients with mild asthma are usually prescribed regular, low-dose inhaled glucocorticoids as controller medications to reduce the risk of exacerbations, with short-acting ß2-agonists (SABAs) used as needed for symptom relief. However, adherence to inhaled glucocorticoids as maintenance therapy is low, and instead these patients overuse SABAs. This overuse is correlated with severe exacerbations or death.
“Patients are often more concerned about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used, than their health care providers, and conversely they are less concerned about their level of symptom control,” wrote the authors of the SYGMA 1 trial, led by Paul M. O’Byrne, MB, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
They added: “Despite the relatively low burden of symptoms in these patients, airway inflammation, although variable in intensity, is usually present.”
In their 52-week, double-blind, multicenter trial, the SYGMA 1 researchers randomly assigned 3,849 patients with mild asthma aged 12 years and older to one of three groups: (1) twice-daily placebo plus terbutaline (0.5 mg) as needed; (2) twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) as needed; and (3) twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) as needed.
The SYGMA 1 team’s primary endpoint was to demonstrate that budesonide-formoterol used as needed was superior to terbutaline used as needed with respect to asthma symptom control, which was measured in weeks of well-controlled disease recorded electronically.
The SYMGA 2 trial, which was also a 52-week, double-blind, multicenter trial, involved 4,215 patients aged 12 years or older randomly assigned to either a budesonide-formoterol or a budesonide maintenance group.
Their primary endpoint was to evaluate whether budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy in terms of annualized frequency of severe exacerbations in either the budesonide-formoterol or the budesonide maintenance groups.
The SYGMA 2 researchers initially wanted to demonstrate the superiority of budesonide-formoterol to budesonide maintenance therapy, but settled for noninferiority due to limitations in sample size. The analysis was adjusted accordingly.
“It was recognized that noninferiority to an effective standard of care in mild asthma (budesonide maintenance therapy), with the use of an alternative treatment approach that would not depend on good adherence, could be clinically relevant,” wrote the SYGMA 2 researchers.
The results of the SYGMA 1 trial indicated that using budesonide-formoterol as needed was superior to terbutaline as needed for both symptom control and the prevention of moderate to severe asthma exacerbations. Furthermore, using budesonide-formoterol as needed was a more effective treatment than SABA alone in patients with mild asthma.
O’Byrne and fellow SYGMA 1 researchers showed that even though budesonide-formoterol as needed had the same efficacy as budesonide maintenance therapy in preventing moderate to severe asthma exacerbations, budesonide-formoterol as needed was worse than budesonide, as measured in weeks with well-controlled asthma. Moreover, compared with maintenance therapy, budesonide-formoterol exposed patients to 17% of the amount of inhaled glucocorticoid burden.
The SYGMA 2 researchers showed that the as-needed use of budesonide-formoterol was noninferior to twice-daily budesonide with respect to severe asthma exacerbations; however, during the treatment period of one year, as-needed use of budesonide-formoterol was worse at symptom control.
As with the SYGMA 1 patients, the SYGMA 2 patients were exposed to lower glucocorticoid burden, with the budesonide-formoterol group experiencing about one-fourth the exposure of the maintenance group.
Taken together, the results of the SYGMA 1 and 2 trials suggest that although budesonide maintenance therapy was best at controlling symptoms of mild asthma, as-needed use of budesonide-formoterol was not worse than budesonide maintenance therapy at preventing severe asthma exacerbations. Furthermore, budesonide-formoterol as needed was more effective than either SABA or terbutaline alone. Finally, one major appeal of using budesonide-formoterol is decreased glucocorticoid burden.
The SYGMA 1 and 2 trials were funded by AstraZeneca.