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Safety of tiotropium in patients with asthma.

ABSTRACT: Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5?µg and 2.5?µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

SUBMITTER: Dusser D

PROVIDER: S-EPMC6391545 | biostudies-literature | 2019 Jan-Dec

REPOSITORIES: biostudies-literature

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Safety of tiotropium in patients with asthma.

Dusser Daniel D Ducharme Francine M FM

Therapeutic advances in respiratory disease 20190101

Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma<sup>®</sup> clinical trial ...[more]

PMID: 30795731

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Project description:BackgroundTiotropium, a once-daily long-acting anticholinergic bronchodilator, when administered via Respimat® SoftMist™ inhaler (tiotropium Respimat®) significantly reduces the risk of severe exacerbations and improves lung function in patients with severe persistent asthma that is not fully controlled despite using inhaled corticosteroids (ICS) and long-acting β2-agonists. To further explore the dose-response curve in asthma, we investigated the efficacy and safety of three different doses of tiotropium Respimat® as add-on to ICS in symptomatic patients with moderate persistent asthma.MethodsIn this randomised, double-blind, placebo-controlled, four-way crossover study, patients were randomised to tiotropium Respimat® 5 μg, 2.5 μg or 1.25 μg or placebo Respimat®, once daily in the evening. Each treatment was administered for 4 weeks, without washout between treatment periods. Eligibility criteria included ≥60% and ≤90% of predicted normal forced expiratory volume in 1 second (FEV1) and seven-question Asthma Control Questionnaire mean score of ≥1.5. Patients were required to continue maintenance treatment with stable medium-dose ICS for at least 4 weeks prior to and during the treatment period. Long-acting β2-agonists were not permitted during the treatment phase. The primary efficacy end point was peak FEV1 measured within 3 hours after dosing (peak FEV1(0-3h)) at the end of each 4-week period, analysed as a response (change from study baseline).ResultsIn total, 149 patients were randomised and 141 completed the study. Statistically significant improvements in peak FEV1(0-3h) response were observed with each tiotropium Respimat® dose versus placebo (all P < 0.0001). The largest difference from placebo was with tiotropium Respimat® 5 μg (188 mL). Trough FEV1 and FEV1 area under the curve (AUC)(0-3h) responses were greater with each tiotropium Respimat® dose than with placebo (all P < 0.0001), and both were greatest with 5 μg. Peak forced vital capacity (FVC)(0-3h), trough FVC and FVC AUC(0-3h) responses, versus placebo, were greatest with tiotropium Respimat® 5 μg (P < 0.0001, P = 0.0012 and P < 0.0001, respectively). Incidence of adverse events was comparable between placebo and all tiotropium Respimat® groups.ConclusionsOnce-daily tiotropium Respimat® add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma. Overall, improvements were largest with tiotropium Respimat® 5 μg.Trial registrationClinicalTrials.gov identifier NCT01233284.

Project description:BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ?2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS:A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P?=?0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P?=?0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS:The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

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Safety of tiotropium in patients with asthma.

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Safety of tiotropium in patients with asthma.

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