Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients.

There remains an unmet need for effective, well-tolerated therapeutic options in paediatric patients with not fully controlled asthma, for whom safety is of paramount importance.Data were pooled from five randomised, double-blind, placebo-controlled studies evaluating tiotropium 5 or 2.5 µg versus placebo add-on therapy in patients with symptomatic asthma aged 1-17 years. Analysis included adverse events (AEs) and serious AEs (SAEs) reported throughout and for 30 days following treatment.Of 1691 patients treated, 1119 received tiotropium. Reporting of AEs was low and comparable across all groups: tiotropium 5 µg (51%), tiotropium 2.5 µg (51%) and placebo (54%). Reporting of drug-related AEs, those leading to discontinuation and SAEs was also low and balanced between treatment groups, irrespective of age, disease severity or sex. The number of AEs related to asthma symptoms and exacerbations was lower with tiotropium (5 µg) than with placebo, particularly during the seasonal peaks of these AEs.This comprehensive analysis of a large safety database allowed subgroup analyses that are often impractical with individual trials and provides further support for the safety of once-daily tiotropium Respimat add-on therapy in paediatric patients with symptomatic asthma.

Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1.

BACKGROUND: The primary lung function endpoint in clinical trials in adolescent and adult patients with asthma is usually forced expiratory volume in one second (FEV1). The objective of our analysis was to assess whether peak expiratory flow (PEF) is a suitable alternative primary lung function endpoint. METHODS: For this assessment, we calculated post hoc the correlation between pre-dose FEV1 and pre-dose PEF measured under supervision in the clinic and, for both lung function parameters, the correlations between supervised clinic and unsupervised home measurements, using the results from the 8 Phase III parallel-group trials of the global clinical development programme with tiotropium Respimat® in patients with asthma aged 12 to 75 years. RESULTS: Across all 8 trials included in this analysis, changes in lung function from baseline correlated well between pre-dose FEV1 and pre-dose PEF when both were measured under supervision in the clinic. Correlation between supervised in-clinic and unsupervised home measurements was stronger for pre-dose PEF than for pre-dose FEV1. CONCLUSIONS: Pre-dose PEF measured at home could be an alternative primary lung function endpoint for trials in adolescent and adult patients with asthma. Using home-measured PEF could facilitate trial conduct and improve the convenience for patients by relocating scheduled assessments from the clinic to the patient's home. TRIAL REGISTRATION: Adolescents aged 12 to 17 years: RubaTinA-asthma® ( NCT01257230 ), PensieTinA-asthma® ( NCT01277523 ). Adults aged 18 to 75 years: GraziaTinA-asthma® ( NCT01316380 ), MezzoTinA-asthma® ( NCT01172808 / NCT01172821 ), CadenTinA-asthma® ( NCT01340209 ), PrimoTinA-asthma® ( NCT00772538 / NCT00776984 ). All from Clinicaltrials.gov ( https://clinicaltrials.gov/ ).

A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma.

BACKGROUND: Studies in adults and adolescents have demonstrated that tiotropium is efficacious as an add-on therapy to inhaled corticosteroids (ICSs) with or without other maintenance therapies in patients with moderate or severe symptomatic asthma. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat add-on therapy to high-dose ICS with 1 or more controller medications, or medium-dose ICS with 2 or more controller medications, in the first phase III trial of tiotropium in children with severe symptomatic asthma. METHODS: In this 12-week, double-blind, placebo-controlled, parallel-group trial, 401 participants aged 6 to 11 years were randomized to receive once-daily tiotropium 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg), or placebo (2 puffs), administered through the Respimat device as add-on to background therapy. RESULTS: Compared with placebo, tiotropium 5 µg, but not 2.5 µg, add-on therapy improved the primary end point, peak FEV1 within 3 hours after dosing (5 µg, 139 mL [95% CI, 75-203; P < .001]; 2.5 µg, 35 mL [95% CI, -28 to 99; P = .27]), and the key secondary end point, trough FEV1 (5 µg, 87 mL [95% CI, 19-154; P = .01]; 2.5 µg, 18 mL [95% CI, -48 to 85; P = .59]). The safety and tolerability of tiotropium were comparable with those of placebo. CONCLUSIONS: Once-daily tiotropium Respimat 5 µg improved lung function and was well tolerated as add-on therapy to ICS with other maintenance therapies in children with severe symptomatic asthma.

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.

Pharmacokinetics of tiotropium administered by Respimat® in asthma patients: Analysis of pooled data from Phase II and III clinical trials.

Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat® inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ss and Cmax,ss. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 µg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 µg once daily or 2.5 µg twice daily via Respimat®). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUCtau,ss) was similar between asthma and COPD, but Cmax,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower Cmax,ss compared to COPD is not considered a concern for tiotropium therapy of asthma.

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.

Magnitude of effect of asthma treatments on Asthma Quality of Life Questionnaire and Asthma Control Questionnaire scores: Systematic review and network meta-analysis.

BACKGROUND: The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment. OBJECTIVE: We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials. METHODS: A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed. RESULTS: Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting ß-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements. CONCLUSION: The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses.

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.).

A randomised dose-ranging study of tiotropium Respimat® in children with symptomatic asthma despite inhaled corticosteroids.

BACKGROUND: A considerable number of children with asthma remain symptomatic despite treatment with inhaled corticosteroids, resulting in significant morbidity, reduced quality of life, increased healthcare costs and lost school days. The aim of our study was to assess the efficacy, safety and tolerability of once-daily tiotropium Respimat® 5 µg, 2.5 µg and 1.25 µg add-on to medium-dose inhaled corticosteroids, with or without a leukotriene modifier, in children aged 6-11 years with symptomatic asthma. METHODS: In this Phase II, double-blind, placebo-controlled, incomplete-crossover, dose-ranging study, patients were randomised to receive three of the four treatments evaluated: once-daily tiotropium Respimat® 5 µg, 2.5 µg or 1.25 µg or placebo Respimat®, in the evening during the 12-week (three × 4-week) treatment period. RESULTS: In total, 76, 74, 75 and 76 patients aged 6-11 years received tiotropium Respimat® 5 µg, 2.5 µg, 1.25 µg and placebo Respimat®, respectively. For the primary end point (peak forced expiratory volume in 1 second measured within 3 hours post-dosing), the adjusted mean responses with tiotropium Respimat® 5 µg (272 mL), 2.5 µg (290 mL) and 1.25 µg (261 mL) were significantly greater than with placebo Respimat® (185 mL; p = 0.0002, p < 0.0001 and p = 0.0011, respectively). The safety and tolerability of all doses of tiotropium Respimat® were comparable with those of placebo Respimat®, with no serious adverse events and no events leading to discontinuation. CONCLUSIONS: Tiotropium Respimat® add-on to medium-dose inhaled corticosteroids, with or without a leukotriene modifier, was efficacious in paediatric patients with symptomatic asthma and had comparable safety and tolerability with placebo Respimat®. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01383499.

Tiotropium Respimat® in asthma: a double-blind, randomised, dose-ranging study in adult patients with moderate asthma.

BACKGROUND: Tiotropium, 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 ß2-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. METHODS: In 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 ß2-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). RESULTS: In 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. CONCLUSIONS: Once-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 REGISTRATION: ClinicalTrials.gov identifier NCT01233284.

Pooled analysis of tiotropium Respimat(®) pharmacokinetics in cystic fibrosis.

Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat(®) in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat(®) across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and ≥ 18 years had similar tiotropium plasma concentrations (geometric mean C(0.083,ss,norm): 2.22 pg/mL/µg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe(0-4,ss): 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients.

Salivette® Cortisol versus oropharyngeal swabbing for the detection of SARS-CoV-2 infection.

BACKGROUND: Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by naso/oropharyngeal swabbing may expose health-care workers to the virus and is technically challenging. The Salivette® is an alternative saliva-collection device with an oral cotton swab containing citric acid to stimulate saliva production, which may have an unpleasant taste. We present a pilot study comparing the Salivette® Cortisol (SC), which uses a synthetic swab without citric acid, against oropharyngeal swabbing for the detection of SARS-CoV-2 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESEARCH DESIGN AND METHODS: Symptomatic SARS-CoV-2-positive patients were sampled at various timepoints. The number of patients positive/negative for SARS-CoV-2 in oropharyngeal swab and SC samples and the percentage of patients testing true positive/true negative for SARS-CoV-2 from SC samples were determined. Positivity was defined by RT-qPCR amplification of 2/3 target SARS-CoV-2 N, ORF1, and S gene sequences. RESULTS: SC demonstrated 100% specificity, 52.2% sensitivity, and positive correlation with oropharyngeal swabbing for the detection of the SARS-CoV-2 S gene. In later-stage disease, lower viral load was observed in SC samples compared with oropharyngeal swabs. CONCLUSIONS: The SC may be an alternative for SARS-CoV-2 detection where naso/oropharyngeal swabbing is not feasible/available. This technique also confirms observations that the detection of SARS-CoV-2 in the upper airway may vary due to viral load over the disease course. TRIAL REGISTRATION: NCT04599959.

Pilot study of an occupational healthcare program to assess the SARS-CoV-2 infection and immune status of employees in a large pharmaceutical company.

OBJECTIVE: To safeguard key workers involved in development and production of medicines and ensure business continuity, we developed an occupational healthcare program, performed by our company's occupational healthcare services, to assess the infection and immune status for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pilot program, conducted at our company facilities, evaluated the suitability of diagnostic tools in our setting for program upscaling. METHODS: We used different marketed in vitro diagnostics (including tests for antibodies against spike protein subunits S1 and S2 and nucleocapsid [N] protein) combined with medical history, symptoms and likelihood of infection. We evaluated the testing strategy over four visits in 141 employees (known positive COVID-19 history, n = 20; unknown status, n = 121) between April and June 2020 at four company locations in Germany. Digital self-monitoring over the pilot program duration was also included. RESULTS: No incident infections were detected. Based on immune status, medical history and likelihood of infection, 10 participants (8.3%) with previously unknown history of COVID-19 were identified to have been infected before entering the program. These participants, who recalled no or mild symptoms in the preceding months, were primarily identified using an assay that detected both S1 and S2 immunoglobulin (Ig) G. The frequency of positive lateral flow assay (LFA) results (IgM or IgG directed against the N-protein) in this cohort was lower compared with participants with a known history of COVID-19 (0‒10.8% vs. 33.8‒75.7%, respectively). CONCLUSIONS: Data from this pilot program suggest that LFA for antibodies may not always reliably detect current, recent or past infections; consequently, these have not been included in our upscaled occupational healthcare program. Regular testing strategies for viral RNA and antibodies directed against different SARS-CoV-2 proteins, combined with hygiene rules and a comprehensive baseline assessment, are recommended to ensure avoidance of infections at workplace as reliably as possible.

Tiotropium Respimat Efficacy and Safety in Asthma: Relationship to Age.

BACKGROUND: Data are limited on the differential response to long-acting bronchodilators in older versus younger adults with asthma. OBJECTIVE: To determine whether the response to tiotropium Respimat differed in older versus younger patients with asthma. METHODS: Post hoc analyses of 4 randomized, double-blind, placebo-controlled studies in adults with asthma were carried out. Two studies compared tiotropium Respimat 5 µg once daily with placebo, both added to high-dose inhaled corticosteroid (ICS) plus long-acting ß2-agonist (ie, severe asthma). The other 2 evaluated tiotropium Respimat 2.5 or 5 µg once daily, salmeterol 50 µg twice daily, or placebo, all added to medium-dose ICS (moderate asthma). Data were analyzed in 2 pools: (1) severe and (2) moderate asthma. Efficacy end points: trough and peak FEV1; trough forced vital capacity; Asthma Control Questionnaire total score and responder percentage, all at week 24. One set of analyses was performed with age as a continuous covariate; the second was conducted in categories less than 40, 40 to 60, and more than 60 years, with treatment-by-age subgroup interaction P values obtained. Safety was analyzed in age categories. RESULTS: Across the age categories, treatment-by-age subgroup interaction P values for trough FEV1 were .13 and .77 for patients with severe and moderate asthma, respectively, not indicating significant impact of age on overall treatment effect, with this observation replicated in the 2 continuum analyses. The other end points (including safety) were also not impacted by age. CONCLUSIONS: Once-daily tiotropium Respimat add-on to ICS or ICS/long-acting ß2-agonist therapy was effective and well tolerated in patients with asthma independent of age.

Forced Expiratory Flow (FEF25-75%) as a Clinical Endpoint in Children and Adolescents with Symptomatic Asthma Receiving Tiotropium: A Post Hoc Analysis.

INTRODUCTION: In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25-75% of the vital capacity (FEF25-75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25-75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. METHODS: Change from baseline in trough FEF25-75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6-11 years) and adolescents (aged 12-17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25-75% and FEV1 were calculated and analyzed. RESULTS: A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25-75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25-75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25-75% showed moderate-to-high correlations (Pearson's correlation coefficients 0.73-0.80). CONCLUSIONS: In pediatric patients, FEF25-75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement.

Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis.

INTRODUCTION: Airway obstruction is usually assessed by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). This post hoc study investigated comparative responses of lung function measurements in adults and adolescents (full analysis set, N = 3873) following treatment with tiotropium Respimat®. METHODS: Lung function outcomes were analysed from five phase III trials in adults (≥ 18 years) with symptomatic severe, moderate and mild asthma (PrimoTinA-asthma®, MezzoTinA-asthma® and GraziaTinA-asthma®, respectively), and one phase III trial in adolescents (12-17 years) with symptomatic moderate asthma (RubaTinA-asthma®). Changes from baseline versus placebo in FEV1, FVC, PEF and FEV1/FVC ratio with tiotropium 5 µg or 2.5 µg added to at least stable inhaled corticosteroids at week 24 (week 12 in GraziaTinA-asthma) were analysed. RESULTS: All lung function measures improved in all studies with tiotropium 5 µg (mean change from baseline versus placebo), including peak FEV1 (110-185 mL), peak FVC (57-95 mL) and morning PEF (15.8-25.6 L/min). Changes in adolescents were smaller than those in adults, and were statistically significant primarily for FEV1 and PEF, but not for FVC. CONCLUSION: Consistent improvements were seen across all lung function measures with the addition of tiotropium to other asthma treatments in adults across all severities, whereas the improvements with tiotropium in adolescents primarily impacted measures of flow rather than lung volume. This may reflect less pronounced airway remodelling and air trapping in adolescents with asthma versus adults.

Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone's breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults.Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

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.