ArticlesTiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials
Introduction
The Global Initiative for Asthma describes the long-term goals of asthma management as achievement of good control and minimisation of future risk of exacerbation, airflow limitation, and side effects.1 However, at least 40% of patients with asthma have poorly controlled disease.2, 3, 4 For patients with moderate asthma who are symptomatic despite the use of inhaled corticosteroids, the recommended options are to increase the dose of corticosteroids or add a long-acting bronchodilator (presently a long-acting β2 agonist [LABA]) to the maintenance treatment regimen, or both.1 If patients remain or subsequently become symptomatic, options are to further increase the dose of inhaled corticosteroids or add further therapeutic treatments such as anti-immunoglobulin E or low-dose oral corticosteroids. However, these approaches do not benefit all patients and can be associated with additional side-effects, such as skin bruising, osteoporosis, cataracts, and anaphylactic reactions.1, 5, 6
Tiotropium—a long-acting anticholinergic bronchodilator—has been investigated as add-on treatment to maintenance therapy with inhaled corticosteroids in patients with uncontrolled or symptomatic asthma. In patients whose asthma was uncontrolled despite continued use of high-dose inhaled corticosteroids and LABA (with other controller drugs permitted), one phase 2 and two large long-term phase 3 studies showed that tiotropium (delivered via the Respimat SoftMist inhaler [Boehringer Ingelheim, Ingelheim am Rhein, Germany]) as add-on to inhaled corticosteroids plus LABA was an effective maintenance therapy for patients with severe disease, providing improvements in lung function7, 8 and reducing the risk of severe exacerbations and asthma worsenings.7, 8
In addition to these studies of severe asthma, in which tiotropium was added to a LABA, two relatively small and short-term studies of moderate asthma have reported non-inferiority between tiotropium and a LABA, each as add-on therapy to low-dose to medium-dose inhaled corticosteroids. The first study9 (the TALC study) was an investigator-initiated, randomised, double-blind, triple-dummy, three-way crossover (14 weeks per treatment) trial in 210 patients with inadequately controlled asthma. Addition of tiotropium (delivered via the dry-powder HandiHaler device [Boehringer Ingelheim, Ingelheim am Rhein, Germany]) to beclomethasone (two puffs of 40 μg twice daily) was associated with improvements in lung function, control, and symptomatic benefit that were greater than when the dose of inhaled corticosteroids was doubled, and, for most outcomes (eg, forced expiratory volume in 1 s [FEV1]), tiotropium was either non-inferior to or better than salmeterol. Until recently, concerns existed regarding the effectiveness of β2 agonists in patients carrying the β2-adrenergic receptor gene polymorphism B16 Arg/Arg. In a phase 2, parallel-group, 16-week, proof-of-concept trial10 in B16-Arg/Arg patients with symptomatic moderate asthma who were receiving medium-dose inhaled corticosteroids (a higher dose than in the TALC study), Bateman and colleagues showed an improvement in mean weekly pre-dose morning peak expiratory flow (PEF) after addition of tiotropium 5 μg that was greater than with placebo and non-inferior to salmeterol.
Evidence from these short-term studies suggests that tiotropium as add-on maintenance therapy might benefit patients with moderate asthma, with effectiveness that is at least similar to that of LABAs. We assessed the safety and efficacy of tiotropium, with salmeterol as active comparator, versus placebo, as add-on therapy to inhaled corticosteroids.
Section snippets
Study design and patients
We did two 24-week, replicate, randomised, double-blind, double-dummy, placebo-controlled, parallel-group studies—MezzoTinA-asthma-1 (trial 1) and MezzoTinA-asthma-2 (trial 2)—at 233 sites in 14 countries (Latvia, Poland, Romania, Russia, Brazil, China, Colombia, Germany, Guatemala, India, Japan, Mexico, Peru, and the USA).
Eligible patients were male or female, aged between 18 and 75 years, and had been diagnosed with asthma before age 40 years and at least 3 months before enrolment. Diagnosis
Results
Figure 1 shows the trial profile. Between Aug 24, 2010, and Nov 13, 2012, we randomly assigned 2103 patients to the tiotropium 5 μg group (n=519), the tiotropium 2·5 μg group (n=520), the salmeterol group (n=541), or the placebo group (n=523; figure 1). The treated set comprised 2100 patients and the full analysis set comprised 2081 patients (figure 1). 1972 (94%) patients completed the study (figure 1). Baseline demographic and disease characteristics were similar between studies and well
Discussion
Our findings show that in patients with moderate asthma who are receiving medium-dose inhaled corticosteroids, addition of once-daily tiotropium significantly improves lung function and asthma control compared with placebo, and has similar efficacy and tolerability to salmeterol. Our findings are consistent with results from previous shorter and smaller studies in patients with moderate asthma9, 10 and with results from studies of tiotropium in patients with severe asthma.7, 8 These findings
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