Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study

SummaryIntroductionTiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat® SoftMist™ inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment.MethodsThis randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 μg, 2.5 μg and 1.25 μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0–3h)).ResultsFrom 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0–3h) response for tiotropium 5 μg was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p = 0.0134) versus placebo, but not for 2.5 μg (p = 0.0975), while FEV1 area under the curve(0–3h) responses were significant for all doses (p = 0.00001–0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity.ConclusionThis first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS.ClinicalTrials.gov identifier; NCT01122680

Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status

AbstractBackgroundMany patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting β2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma.ObjectiveTo determine whether the efficacy of tiotropium add-on therapy is dependent on patients’ baseline characteristics.MethodsTwo randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat® 5 μg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics.Results912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility.ConclusionOnce-daily tiotropium 5 μg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma.Trial registryClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov

A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma

We present results from the first phase III trial of once-daily tiotropium add-on to inhaled corticosteroids (ICS) plus one or more controller therapies in adolescents with severe symptomatic asthma.In this double-blind, parallel-group trial (NCT01277523), 392 patients aged 12-17\u2005years were randomised to receive once-daily tiotropium 5\u2005\ub5g or 2.5\u2005\ub5g, or placebo, as an add-on to ICS plus other controller therapies over 12\u2005weeks. The primary and key secondary end-points were change from baseline (response) in peak forced expiratory volume in 1\u2005s (FEV1) within 3\u2005h post-dosing (FEV1(0-3h)) and trough FEV1, respectively, after 12\u2005weeks of treatment.Tiotropium 5\u2005\ub5g provided numerical improvements in peak FEV1(0-3h) response, compared with placebo (90\u2005mL; p=0.104), and significant improvements were observed with tiotropium 2.5\u2005\ub5g (111\u2005mL; p=0.046). Numerical improvements in trough FEV1 response and asthma control were observed with both tiotropium doses, compared with placebo. The safety and tolerability of tiotropium were comparable with those of placebo.Once-daily tiotropium Respimat add-on to ICS plus one or more controller therapies in adolescents with severe symptomatic asthma was well tolerated. The primary end-point of efficacy was not met, although positive trends for improvements in lung function and asthma control were observed

Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype

BACKGROUND: Adding tiotropium to existing inhaled corticosteroid (ICS) maintenance therapy with or without a long-acting β2-agonist (LABA) has been shown to be beneficial in patients with symptomatic asthma. OBJECTIVE: To assess whether responses to tiotropium Respimat add-on therapy were influenced by patients' T2 status. METHODS: In this exploratory study, data from 4 phase III trials were analyzed: once-daily tiotropium 5 μg or placebo as add-on to ICS + LABA (PrimoTinA-asthma; 2 replicate trials; NCT00772538/NCT00776984; n = 912); once-daily tiotropium 5 μg or 2.5 μg, twice-daily salmeterol 50 μg, or placebo as add-on to ICS (MezzoTinA-asthma; 2 replicate trials; NCT01172808/NCT01172821; n = 2100). The prespecified efficacy outcomes of these studies have been reported previously. Here, further exploratory subgroup analyses were performed to study whether these coprimary end points were influenced by serum IgE levels, blood eosinophil counts, and clinician judgment of allergic asthma. In addition, for the continuous parameters, namely, IgE and blood eosinophils, their influence on the treatment effect was modeled over the whole range of values. RESULTS: Tiotropium was efficacious in improving peak FEV1 within 3 hours postdose and trough FEV1, independent of T2 status. Tiotropium significantly reduced the risk of severe asthma exacerbations and asthma worsening, independent of T2 phenotype; Cox regression modeling supported a beneficial effect of tiotropium on exacerbations, independent of IgE levels or eosinophil counts. Numerical improvements in the 7-question Asthma Control Questionnaire (ACQ-7) responder rate with tiotropium versus placebo were observed in T2high and T2low patients; logistic regression modeling provided further evidence for improvement in ACQ-7 responder rates with tiotropium, independent of IgE levels or eosinophil counts. CONCLUSIONS: The results of our exploratory analyses suggest that the improvements seen with tiotropium Respimat as add-on to ICS ± LABA in patients with symptomatic asthma on lung function, exacerbation risk, and symptom control are independent of T2 phenotype

Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy

BACKGROUND Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs). METHODS In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 mu g) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV1) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. RESULTS The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (+/- SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86 +/- 34 ml in trial 1 (P=0.01) and 154 +/- 32 ml in trial 2 (P CONCLUSIONS In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.