Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms. METHODS: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 µg, tiotropium 5 µg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 µg in the 2·5 µg group, two puffs of 2·5 µg in the 5 µg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed. FINDINGS: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 µg, 32 to receive tiotropium 5 µg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 µg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 µg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 µg, 18 [58%] of 31 with tiotropium 5 µg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 µg group and two [6%] of 31 in the 5 µg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death. INTERPRETATION: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children. FUNDING: Boehringer Ingelheim.

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 ß2-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.

Efficacy and safety of beclomethasone dipropionate breath-actuated or metered-dose inhaler in pediatric patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for hand-breath coordination and, therefore, simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI and metered-dose inhaler (MDI) versus placebo in pediatric patients ages 4-11 years with persistent asthma. METHODS: In this double-blind, double-dummy, phase III study, 628 children with persistent asthma were randomly assigned (1:1:1:1:1) to twice-daily beclomethasone dipropionate (BAI 80 µg/day, BAI 160 µg/day, MDI 80 µg/day, or MDI 160 µg/day) or to placebo. Efficacy over 12 weeks was assessed by spirometry, peak expiratory flow (PEF) measurements and other clinical end points. The primary efficacy end point was the baseline-adjusted trough morning percent predicted forced expiratory volume in 1 second (PPFEV1) area under the effect curve from 0 to 12 weeks (AUEC[0-12 weeks]). RESULTS: PPFEV1 AUEC(0-12 weeks) showed numerical improvements from baseline in the BAI 80 µg/day and BAI 160 µg/day groups and MDI 80 µg/day and MDI 160 µg/day groups; however, these improvements were not significant versus placebo for any group after hierarchical testing was applied. Consistent improvements were noted in the active treatment groups versus placebo for the weekly average trough morning and evening PEFs, and with BAI 80 µg/day versus placebo for rescue albuterol/salbutamol use and the total daily asthma symptom score. Most patients indicated that the BAI device was easy or very easy to use. Adverse events were comparable across the groups; the incidence of oral candidiasis ranged from 0.8 to 3.2%. CONCLUSIONS: Although the primary efficacy end point was not demonstrated, consistent improvements in PEF and other clinical end points were observed with beclomethasone dipropionate BAI, particularly at the 80 µg/day dose. These clinical benefits, combined with the need for better symptom control in children with asthma, supported the development of beclomethasone dipropionate BAI.

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 years were randomised to receive once-daily tiotropium 5 µg or 2.5 µg, or placebo, as an add-on to ICS plus other controller therapies over 12 weeks. The primary and key secondary end-points were change from baseline (response) in peak forced expiratory volume in 1 s (FEV1) within 3 h post-dosing (FEV1(0-3h)) and trough FEV1, respectively, after 12 weeks of treatment.Tiotropium 5 µg provided numerical improvements in peak FEV1(0-3h) response, compared with placebo (90 mL; p=0.104), and significant improvements were observed with tiotropium 2.5 µg (111 mL; 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 improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status.

BACKGROUND: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting ß2-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. OBJECTIVE: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics. METHODS: Two 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. RESULTS: 912 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. CONCLUSION: Once-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 REGISTRY: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov.

Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial.

BACKGROUND: Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid (ICS) maintenance therapy. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma. METHODS: In this 48-week, double-blind, placebo-controlled, parallel-group study, 398 patients aged 12 to 17 years were randomized to receive 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to ICS background therapy, with or without a leukotriene receptor antagonist; long-acting ß2-agonist therapy was not permitted during the study. RESULTS: Improvement in peak FEV1 within 3 hours after dosing at 24 weeks (primary end point) was statistically significant with both tiotropium doses compared with placebo: 5 µg of tiotropium, 174 mL (95% CI, 76-272 mL); 2.5 µg of tiotropium, 134 mL (95% CI, 34-234 mL). Significant improvements in trough FEV1 at week 24 (a secondary end point) were observed with the 5-µg dose only. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed. CONCLUSIONS: Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma. Larger responses were observed with the 5-µg tiotropium dose.

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

INTRODUCTION: Tiotropium, 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. METHODS: This 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)). RESULTS: From 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. CONCLUSION: This 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 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 µg) 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 (FEV(1)) 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 FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) 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<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups. 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.).

Fluticasone furoate nasal spray is more effective than fexofenadine for nighttime symptoms of seasonal allergy.

Nasal symptoms of allergic rhinitis are an important cause of sleep disturbance. Reduction of nasal symptoms, particularly nasal obstruction, has been linked to improvements in self-reported sleep quality. The enhanced-affinity intranasal corticosteroid fluticasone furoate and the oral antihistamine fexofenadine were compared with respect to nighttime symptoms of seasonal allergic rhinitis. In two randomized, double-blind, double-dummy, parallel-group studies, patients received fluticasone furoate nasal spray (FFNS),110 microg (study 1, n = 312; study 2, n = 224); fexofenadine, 180 mg (study 1, n = 311; study 2, n = 227); or placebo (study 1, n = 313; study 2, n = 229) once daily for 2 weeks. Fluticasone furoate was more effective (p < 0.001) than fexofenadine and placebo in both studies with respect to the mean changes from baseline over the treatment period in the nighttime symptoms score, nighttime reflective total nasal symptom score, predose instantaneous nasal symptom score, and morning peak nasal inspiratory flow. Fluticasone furoate was more effective than placebo (p

Facial angioedema in children due to ladybug (Harmonia axyridis) contact: 2 case reports.

BACKGROUND: Only 9 adult cases of immediate-hypersensitivity reaction to ladybugs, also known as Asian lady beetles (Harmonia axyridis), have been documented in the literature. These patients have all shown symptoms of allergic rhinoconjunctivitis or asthma from exposure to ladybugs. OBJECTIVE: To describe the first pediatric patients with severe allergic facial angioedema requiring emergency department management after exposure to ladybugs. METHODS: Evidence of IgE-mediated hypersensitivity to ladybugs was documented by positive skin prick test reactions, correlating with exposure history. RESULTS: Two cases in preschool boys had similar features, although they were evaluated and tested by 2 different allergists. Both patients developed severe facial or periocular angioedema with no significant respiratory involvement after exposure to ladybugs outside their infested homes. Both patients required an emergency department visit for treatment. Allergy evaluation using ladybug extract for skin prick testing showed markedly positive reactions in both patients. There were no further episodes after environmental control measures were instituted. CONCLUSIONS: Although allergic respiratory or cutaneous reactions to ladybugs are uncommon, a high index of suspicion from exposure history and confirmatory skin testing can be conclusive for the diagnosis.