Objective: to evaluate whether addition of formoterol to treatment with budesonide in patients with asthma is associated with an increased risk of asthma-related serious adverse events (SAEs) and whether it improves asthma control.
Design: double-blind randomised control trial (RCT). The protocol was developed in discussion with the Food and Drug Administration (FDA) of the United States.
Setting: 534 centres in 25 countries in Europe, Africa, Asia and America.
Study sample: patients aged more than 12 years with a clinical diagnosis of asthma and at least one exacerbation in the previous year (but none in the previous month). Patients were eligible if they were being treated with an inhaled glucocorticoid (IG) alone or combined with a long-acting β-agonist, or their disease severity or level of asthma control warranted such treatment. Exclusion criteria: history of life-threatening asthma, more than four exacerbations or two asthma-related hospitalizations in the previous year, poor symptom control in the seven days preceding randomization, or smoking history of more than 10 pack-years. A total of 11 693 patients underwent randomization, of who 11 551 completed the study, but all were included in the intention-to-treat analysis.
Treatment based on severity and level of control: patients were stratified to a dose level of budesonide (80 or 160 μg every 12 hours). Patients were randomly assigned in a 1:1 ratio within their stratum to receive formoterol (4.5 μg) administered through the same inhaler as budesonide (treatment group [TG]) or budesonide alone (control group [CG]) for a period of 26 weeks. Adherence was assessed by means of the dose-actuation counter on each inhaler. The followup consisted of three in-person clinical visits (at 4, 12 and 26 weeks) and monthly telephone calls.
Study endpoints: the primary endpoint was the risk of asthma-related SAE (death, intubation or hospitalization) and the time to the first such event. Other safety assessments: death from any cause, discontinuations resulting from adverse events, and discontinuations resulting from exacerbations. The secondary objective of the study was to evaluate efficacy based on the time to the first exacerbation requiring treatment with glucocorticoids for at least three days, inpatient hospitalization or prescription of glucocorticoids by an emergency department. Secondary efficacy variables: assessment of current asthma control based on the Asthma Control Questionnaire (ACQ-6) and data from patient diaries (use of rescue medication and frequency of symptoms). The primary endpoint was assessed using a two-sided test in which non-inferiority was concluded if the upper limit of the 95% confidence interval (95 CI) for the hazard ratio was less than 2.0. Safety data were collected at the end of the study or up to seven days after the last dose. Data on efficacy variables were collected up to seven days after the last dose and assessed in patients stratified by level of control at study entry and by IG dose level.
Main results: the two groups had similar baseline characteristics: at study entry, 9.9% were not using IGs and 40.9% had uncontrolled asthma. Approximately 80% of all patients had 80% or more adherence to the regimen. Asthma-related SAEs occurred in 43 patients in the TG and 40 patients in the CG, and two of the SAEs were asthma-related deaths, both in the TG. Statistical noninferiority was demonstrated for the time to first serious asthma-related event: hazard ratio (HR), 1.07 (95 CI, 0.7-1.65), with similar results in the GI low-dose and high-dose subgroups. As for efficacy, the study found a lower risk of exacerbation in the TG (HR, 0.84; 95 CI, 0.74-0.94) with improved asthma control based on patient diaries and the ACQ-6.
Conclusion: among patients aged more than 12 years with moderate to severe asthma, treatment with budesonide-formoterol was associated with a lower risk of exacerbations compared to treatment with budesonide alone, with a similar risk of asthma-related SAEs.
Conflicts of interest: most authors have received funding from AstraZeneca and other pharmaceutical companies.
Funding source: AstraZeneca.