Budesonide-formoterol as needed superior to terbutaline in mild asthma: The SYGMA trial
1. In patients with mild asthma, use of the inhaled combined corticosteroid (ICS) and beta agonist budesonide-formoterol as needed was superior to terbutaline as needed with respect to electronically recorded weeks of well-controlled asthma.
2. While budesonide-formoterol as needed was inferior to twice daily budesonide maintenance therapy with respect to weeks of well-controlled asthma, there was no significant difference in rates of exacerbations.
Study Rundown: Low symptom burden and sporadic nature of exacerbations often make adherence to ICS maintenance therapy challenging in patients with mild asthma. When this produces over-dependence on short-acting beta agonists (SABA) for symptom relief, airway inflammation goes untreated and patients are at risk for future exacerbations. In the SYmbicort Given as needed in Mild Asthma (SYGMA) trial, efficacy and safety of budesonide-formoterol (a combination ICS and beta-agonist) on an as needed basis was comparted to both the beta-agonist terbutaline as needed and with maintenance budesonide plus terbutaline as needed. The primary endpoint, superiority of as needed budesonide-formoterol to terbutaline with regard to electronically recorded weeks of well-controlled asthma, demonstrated a greater percentage of weeks with asthma control over a 52 week period for budesonide-formoterol patients. However, budesonide-formoterol was inferior to budesonide maintenance therapy with regard to weeks of well-controlled asthma (secondary endpoint).
A strength of this randomized, double-blind, 52-week, parallel group trial was the long duration, which allowed reliable assessment of asthma exacerbations. The study also used a 2-4 week run-in period to collect baseline data and ensure subjects required step 2 asthma treatment. Though the high rate of adherence in the trial allowed appropriate comparison with budesonide maintenance therapy, it limits the generalizability to the real-world population where adherence rates may be lower.
Relevant Reading: Daily versus as-needed corticosteroids for mild persistent asthma
In-Depth [randomized controlled trial]: This was a phase III, double-blind, parallel-group, multicenter trial that randomized 3849 patients to twice daily placebo plus budesonide-formoterol (200 mg of budesonide and 6 mg formoterol) as needed (n = 1279), twice-daily placebo plus terbutaline (0.5 mg) as needed (n = 1280), or twice daily budesonide (200 mg) maintenance therapy plus terbutaline (0.5 mg) as needed (n = 1290). Eligible patients were 12 or older and had clinically mild asthma. Patients with exacerbations or long-term poor control were permitted to receive additional open-label treatment with twice daily budesonide (200 mg) at the investigator's discretion. The primary endpoint was to demonstrate superiority of budesonide-formoterol as needed compared to terbutaline as needed for asthma control, measured by electronically recorded weeks with well-controlled asthma over a 52-week period. Secondary endpoint included noninferiority of budesonide-formoterol to budesonide maintenance therapy, rates of severe exacerbations and time to the first severe exacerbation, and Asthma-Control Questionnaire-5 (ACQ-5) score.
Patients in the budesonide-formoterol as needed group had well-controlled asthma 34.4% of weeks, compared to 31.1% in the terbutaline group (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.00 to 1.30; p = 0.046). This percentage was inferior compared to budesonide maintenance therapy (34.4% vs. 44.4%; OR, 0.64; 95%CI, 0.57 to 0.73). Budesonide-formoterol resulted in a 64% lower rate of severe exacerbations compared to terbutaline (annual exacerbation rate, 0.07 vs. 0.20; rate ratio, 0.36; 95%CI, 0.27 to 0.49) and also the time to the first severe exacerbation (hazard ratio [HR], 0.44; 95%CI, 0.33 to 0.58). Neither rates of severe exacerbations nor time to first exacerbation differed significantly between budesonide-formoterol as needed and budesonide maintenance therapy. Differences in the change in the ACQ-5 score were in favor of the budesonide-formoterol group compared to terbutaline, and in favor of budesonide maintenance compared to budesonide-formoterol. Adverse events were more frequent in the terbutaline as needed group, but there were no notable differences in the side effect profile between treatment groups.
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