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Tiotropium 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

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Summary

Background

In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids.

Methods

We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18–75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60–90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Patients and study investigators were masked to treatment allocation. Prespecified co-primary endpoints, assessed at week 24 in the full analysis set, were peak FEV1 response, measured within the first 3 h after evening dosing; trough FEV1 response; and responder rate assessed according to the seven-question Asthma Control Questionnaire (ACQ-7). These studies are registered with ClinicalTrials.gov, numbers NCT01172808 and NCT01172821.

Findings

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); 1972 (94%) patients completed the study. Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies. With pooled data, difference versus placebo in peak FEV1 was 185 mL (95% CI 146–223) in the tiotropium 5 μg group, 223 mL (185–262) in the tiotropium 2·5 μg group, and 196 mL (158–234) in the salmeterol group (all p<0·0001); difference in trough FEV1 was 146 mL (95% CI 105–188), 180 mL (138–221), and 114 mL (73–155; all p<0·0001), respectively. There were more ACQ-7 responders in the tiotropium 5 μg (OR 1·32, 95% CI 1·02–1·71; p=0·035) and 2·5 μg (1·33, 1·03–1·72; p=0·031) groups, and the salmeterol group (1·46, 1·13–1·89; p=0·0039), than in the placebo group. 48 (2%) of 2100 patients had serious adverse events (tiotropium 5 μg n=11, tiotropium 2·5 μg n=12, salmeterol n=11, placebo n=14).

Interpretation

Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma. Patterns of response with both tiotropium doses were similar to those of salmeterol, and all active compounds had good safety and tolerability. Tiotropium is a safe and effective bronchodilator, and an alternative to salmeterol in this patient population.

Funding

Boehringer Ingelheim.

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

References (27)

  • ED Bateman et al.

    Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study

    Am J Respir Crit Care Med

    (2004)
  • BA Chowdhury et al.

    The FDA and safe use of long-acting beta-agonists in the treatment of asthma

    N Engl J Med

    (2010)
  • HAM Kerstjens et al.

    Tiotropium in asthma poorly controlled with standard combination therapy

    N Engl J Med

    (2012)
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    See appendix for full list of trial investigators

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