Tiotropium bromide step-up therapy for adults with uncontrolled asthma

Abstract

Background: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed.

Methods: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison).

Results: The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003).

Conclusions: When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

Figure 1. Enrollment and Outcomes

The TALC and BASALT studies were companion trials that used a common run-in period: patients with better-controlled asthma were assigned to the BASALT trial, and those with poorer control were assigned to the TALC trial. Shown are the numbers of patients who enrolled in the common run-in period, those who underwent randomization to each study, and those who completed the TALC study. At the start of the recruitment period, TALC study drugs were not yet available, which accounted for the 57 patients who were assigned before the TALC start date, and randomization of patients to the TALC trial ended before all patients were assigned to the BASALT trial, which accounted for the 22 patients who were assigned after TALC recruitment closed.

Figure 2. Outline of Study Protocol

Shown are the durations of the common run-in, treatment, and washout periods, along with periods in which baseline data for variables that were collected daily were obtained before each treatment period. During the 4-week run-in period and the 2-week washout periods, all patients received beclomethasone at a dose of 80 μg (2 puffs of 40 μg) twice daily. Only three of the six possible treatment sequences are presented graphically.

Figure 3. Primary and Secondary Outcomes

Shown are the mean differences among patients receiving tiotropium, those receiving double-glucocorticoid, and those receiving salmeterol with respect to the morning peak expiratory flow (PEF) (Panel A), the evening PEF (Panel B), the prebronchodilator forced expiratory volume in 1 second (FEV₁) (Panel C), and the proportion of asthma-control days per 14-day period (Panel D). The I bars indicate 95% confidence intervals.