Abstract
BackgroundIn many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol ‘as needed’ in response to symptoms may represent an alternative treatment option for patients with mild asthma.Methods/designThe SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors.DiscussionGiven the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017.Trial registrationClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively.
Highlights
In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult
Sample size estimates In SYGMA1, 3750 patients (625 patients/treatment group/pre-study treatment group) are required to give greater than 95% power to detect superiority of as-needed budesonide/formoterol compared with as-needed terbutaline and 90% power to establish noninferiority of asneeded budesonide/formoterol compared with budesonide plus as-needed terbutaline for well-controlled asthma weeks, with a pre-defined noninferiority limit of 0.8, i.e. the lower 95% confidence interval (CI) of the odds ratio for budesonide/formoterol versus budesonide plus terbutaline is ≥0.8
SYGMA2 was initially powered to demonstrate superiority of as-needed budesonide/formoterol compared with budesonide plus as-needed terbutaline as measured by the annualised severe exacerbation rate; 4114 patients (2057 patients/treatment group) were estimated to be required to achieve 90% power to detect a difference in annualised severe asthma exacerbation rate between treatments, assuming an exacerbation rate of 0.16 per year among patients treated with budesonide, with a 25% reduction in risk for patients receiving as-needed budesonide/formoterol
Summary
Both clinicians and patients may underestimate the risks and burden associated with mild asthma. In SYGMA1 only, patient recruitment will be balanced to allow stratification based on pre-study treatment, i.e. asthma that is uncontrolled on as-needed short-acting bronchodilator or asthma that is well-controlled on mono-maintenance with either a low-dose ICS or LTRA plus as-needed short-acting bronchodilator. The use of regular daily low-dose budesonide is wellestablished, having been shown to be highly effective in reducing the risk of asthma-related exacerbations, including in patients with mild persistent asthma (as demonstrated in the START study) [3]. The availability of an as-needed ICS/LABA single inhaler that could provide comparable control to current standard-of-care treatment with low-dose daily ICS plus asneeded medication would represent a breakthrough in the treatment of mild asthma, providing patients and clinicians with an alternative more convenient option with the potential for improved adherence.
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