Tiotropium Respimat Research Articles

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics

IntroductionLoss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. MethodsWe performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. ResultsThe average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). ConclusionLAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

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

IntroductionIn 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.MethodsChange 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.ResultsA 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).ConclusionsIn 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.Electronic Supplementary MaterialThe online version of this article (10.1007/s41030-020-00117-6) contains supplementary material, which is available to authorized users.

Tiotropium Respimat Efficacy and Safety in Asthma: Relationship to Age

Data are limited on the differential response to long-acting bronchodilators in older versus younger adults with asthma. To determine whether the response to tiotropium Respimat differed in older versus younger patients with asthma. 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 β2-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 60years, with treatment-by-age subgroup interaction P values obtained. Safety was analyzed in age categories. 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. Once-daily tiotropium Respimat add-on to ICS or ICS/long-acting β2-agonist therapy was effective and well tolerated in patients with asthma independent of age.

The Design of and Rationale for the Effect of Perioperative Inhaled Tiotropium for Patients with Chronic Obstructive Pulmonary Disease in Esophageal Cancer Surgery (EPITOPE): an Open-Label, Randomized, Parallel-Group Study

Introduction: Pneumonia is one of the most frequently occurring complications after esophagectomy and is associated with increased operative mortality. Chronic obstructive pulmonary disease (COPD) is known to be a risk factor for pulmonary complications and operative mortality. However, in COPD patients preparing for esophagectomy, preventive measures against postoperative pneumonia have not yet been discovered. In this study, we evaluate the effect of perioperative inhaled tiotropium, a long-acting, antimuscarinic bronchodilator used in the management of COPD, on patients with COPD who undergo esophageal cancer surgery. Methods/Design: This study investigates the effect of perioperative inhaled tiotropium on patients with COPD who undergo esophagectomy. It is an open-label, randomized controlled trial conducted in a single center (EPITOPE study). A total of 32 enrolled patients are randomly assigned in a 1:1 ratio to either conventional management or inhalation of tiotropium in addition to the conventional management. Patients included in the intervention group receive tiotropium Respimat 5 μg (two inhalations of 2.5 μg) for at least 2 weeks before the esophagectomy. Following the esophagectomy, tiotropium is re-delivered, starting as early as possible and continuing until the postoperative evaluation (between 30 and 44 days after the operation). The primary outcome is the incidence of pneumonia within 30 days after esophagectomy. Secondary outcomes are the incidence of cardiovascular complications within 30 days after esophagectomy, the incidence of any postoperative complications within 30 days after esophagectomy, pulmonary function (preintervention, preoperative, and postoperative), walking distance in the incremental shuttle walking test (preintervention, preoperative, and postoperative), the incidence of adverse events, and mortality within 30 days after esophagectomy. Discussion: The EPITOPE study is the first pilot study on the effects of perioperative inhaled tiotropium on patients with COPD undergoing esophagectomy. After completing this study, we will plan a multicenter RCT with the appropriate outcomes in the future.

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

IntroductionAirway 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®.MethodsLung 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.ResultsAll 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.ConclusionConsistent 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.

A rational approach to the treatment of bronchial asthma in children: what can we do to control the disease?

Bronchial asthma is the most common among chronic bronchopulmonary diseases with heterogeneity in symptom profiles. Despite the delivery of baseline anti-inflammatory iGCS therapy, including the subsequent staged addition of other controlling treatment methods, symptoms of the disease persist in 40% of patients. Lack of asthma control results in high morbidity, mortality and treatment costs, which justifies the search for new therapeutic options to improve control and reduce the risk of future exacerbations. Tiotropium, a long-acting anticholinergic bronchodilator, can be a good alternative in the therapeutic treatment of poorly controlled asthma in both adults and children. Several clinical studies showed the efficacy and safety of Tiotropium Respimat Soft Mist Inhaler at a dose of 5 mg in various asthma treatment options in children at 6 years old and over, who do not achieve asthma control with iGCS monotherapy at medium/high doses or with iGCS/LABA combination at medium/high doses. All asthma studies in children were conducted using Respimat Soft Mist Inhalers that generate an aerosol with a larger number of small particles, which ensures effective drug distribution and deposition in the lungs. The aerosol cloud velocity at the nozzle outlet of the inhaler is just 0.8 m/s, and the time period over which the aerosol is released is extended to 1.5 s. Moving slowly, aerosol particles more often avoid colliding with the posterior pharyngeal wall and tongue, which reduces the drug deposition in the oral cavity, significantly increasing the amount of active substance delivered to the air ways. 55% of the dose of tiotropium bromide is released in the form of particles with an optimal aerodynamic diameter, which guarantees a high level of lung deposition - 52% of the ex-valve dose.

Efficacy of once-daily tiotropium Respimat in adults with asthma at GINA Steps 2–5

Tiotropium Respimat is an efficacious add-on to maintenance treatment in patients with symptomatic asthma. Currently, the Global Initiative for Asthma (GINA) strategy recommends tiotropium for patients at Steps 4–5. To assess the clinical benefits of tiotropium Respimat across asthma severities, GINA Steps 2–5, a post hoc analysis of five double-blind trials (12–48-weeks; patients aged 18–75 years) investigated the effect of tiotropium Respimat, 5 μg or 2.5 μg, versus placebo, on peak forced expiratory volume in 1 s (FEV1) within 3 h post-dose (FEV1(0–3h)) response, and Asthma Control Questionnaire-7 (ACQ-7) responder rate. GINA step grouping was based on patients’ background treatment regimen. Baseline characteristics of patients (N = 2926) were balanced between treatments. Tiotropium Respimat showed consistent improvements in lung function across GINA steps; placebo-corrected peak FEV1(0–3h) improvements after tiotropium Respimat 5 μg and 2.5 μg were: Step 2 (Week 8), 135 mL (95% confidence interval: 84, 187) and 155 mL (103, 206); Step 3 (Week 24), 187 mL (139, 235) and 235 mL (187, 283); Step 4 (Week 24), 111 mL (63, 159) and 181 mL (35, 326); Step 5 (Week 24; 5 μg only), 164 mL (5, 323). Asthma control improved with tiotropium Respimat versus placebo, showing statistical significance (nominal P value) with tiotropium Respimat 5 μg at Step 4 (odds ratio 1.36 [1.03, 1.78]). Safety profiles were similar between treatments. In conclusion, tiotropium Respimat add-on therapy improves lung function, and may improve asthma control, in adults across disease severities.

Tiotropium Respimat® add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics

Despite currently available therapies and detailed treatment guidelines, many patients with asthma remain symptomatic. Tiotropium delivered by the soft mist inhaler Respimat®, as add-on therapy to medium-dose inhaled corticosteroids (ICS), has been shown to improve lung function and asthma control in patients with symptomatic moderate asthma. To determine whether the efficacy of tiotropium Respimat® in asthma differs by patients' study baseline characteristics. Two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group studies (MezzoTinA-asthma®; NCT01172808 and NCT01172821) of once-daily tiotropium Respimat 5 μg and 2.5 μg add-on to ICS were conducted in patients with symptomatic asthma despite treatment with medium-dose ICS with or without additional controllers. Subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, risk of severe asthma exacerbation and Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by patients' baseline characteristics. In this analysis, 523 patients received placebo while 517 and 519 patients received the 5 μg and 2.5 μg dose of tiotropium Respimat, respectively. The magnitude of the improvements in lung function and asthma control, as well as the reduced risk of severe exacerbation with both doses of tiotropium Respimat versus placebo, was independent of a broad range of baseline characteristics. Once-daily tiotropium Respimat as add-on to ICS is a beneficial treatment option for patients with asthma who remain symptomatic despite at least medium-dose ICS, regardless of baseline characteristics.

Burden of Asthma and Role of 2.5µg Tiotropium Respimat® as an Add-On Therapy: A Systematic Review of Phase 2/3 Trials.

IntroductionTiotropium, a long-acting muscarinic antagonist, is approved for maintenance treatment of asthma in patients at least 6 years of age in the USA. We systematically reviewed published evidence on the efficacy and safety of 2.5 µg tiotropium Respimat® add-on therapy to inhaled corticosteroid (ICS) with or without additional controller medication(s) in children, adolescents, and adults with asthma.MethodsWe searched PubMed from inception until October 3, 2018, for phase 2 and 3 randomized controlled trials (RCTs) evaluating the effects of 2.5 µg tiotropium Respimat® on lung function parameters in patients with asthma. We extracted adjusted mean differences for lung function data and adverse events (AEs) from relevant articles.ResultsOverall, 11 RCTs (three phase 2 and eight phase 3 studies) including 3244 patients (2.5 µg tiotropium Respimat®, n = 1642; placebo, n = 1602) met the predefined inclusion criteria. Once-daily 2.5 µg tiotropium Respimat® improved lung function parameters, including peak and trough forced expiratory volume in 1 s and peak and trough forced vital capacity, versus placebo. Overall, the safety profile of 2.5 µg tiotropium Respimat® was comparable to that of placebo, with the most commonly reported AEs being asthma worsening, reduction in peak expiratory rate, nasopharyngitis, and respiratory tract infections.ConclusionOn the basis of the results of phase 2 and 3 studies, 2.5 µg tiotropium Respimat® as add-on to ICS therapy was safe and associated with consistent improvements in lung function in patients with asthma of varying severities across different age groups.FundingDevelopment of the manuscript was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01062-w) contains supplementary material, which is available to authorized users.

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

BackgroundThe 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.MethodsFor 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.ResultsAcross 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.ConclusionsPre-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 registrationAdolescents 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/).

Future perspectives of anticholinergics for the treatment of asthma in adults and children.

Despite major advances in therapeutic interventions and the availability of detailed treatment guidelines, a high proportion of patients with symptomatic asthma remain uncontrolled. Asthma management is largely guided by the Global Initiative for Asthma (GINA) strategy and is based on a backbone of inhaled corticosteroid (ICS) therapy with the use of additional therapies to achieve disease control. Inhaled long-acting bronchodilators alone and in combination are the preferred add-on treatment options. Although long-acting muscarinic antagonists (LAMAs) are a relatively recent addition to disease management recommendations for asthma, tiotropium has been extensively studied in a large clinical trial program. In Europe and the United States, tiotropium is approved for patients aged ≥6 years and uncontrolled on medium- to high-dose ICS/long-acting β2-agonists at GINA Steps 4 and 5 with a history of exacerbations. Evidence supports the efficacy of tiotropium Respimat® in adults in terms of lung function and asthma control, with a safety profile comparable with that of placebo across a range of asthma severities. Similarly, clinical trials in patients aged 1–17 years have shown improvements in lung function and trends toward improved asthma control. Furthermore, its efficacy makes tiotropium relatively easy to incorporate into routine clinical practice, irrespective of allergic status and without the need for patient phenotyping. Tiotropium is a cost-effective treatment that may offer an important alternative to other, more expensive add-on therapies. This review discusses the potential future position of LAMAs in clinical practice by considering the continuously evolving evidence. Prominence is given to tiotropium, the only LAMA supported by a structured clinical trial program in asthma to date, while also considering other recommended treatment options for patients with uncontrolled asthma. The importance of effective patient/caregiver–clinician communication and shared decision-making in enhancing treatment adherence is also highlighted.

New possibilities for asthma therapy in children

This article discusses issues of clinical diagnosis and course of bronchial asthma in children. We discuss assessment of asthma severity and, accordingly, the extent of the step-by-step therapy according to updated recommendations (GINA 2018). Particular attention is paid to the possibility of improving the control of asthma with the help of the M-cholinolytic drug of long-acting tiotropium bromide, presented as a special inhalation form of tiotropium Respimat and registered in the Russian Federation for treatment of asthma in children of moderate and severe course from 6 years of age. Application tiotropium Respimat in children with insufficient control of asthma allows to improve lung function and asthma control.

A Single Institution Retrospective Study of the Clinical Efficacy of Tiotropium Respimat in Never-Smoking Elderly Asthmatics with Irreversible Airflow Limitation.

In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium RespimatⓇ (Tio-Res) in symptomatic, never-smoking, elderly asthmatics with irreversible airflow limitation despite the use of high-dose inhaled corticosteroids (ICS) plus long-acting β2-adrenoceptor agonists (LABA). The Asthma Control Test™ (ACT), pulmonary function tests, morning and evening peak flow (mPEF, ePEF, respectively, evaluated with an ASSESS® peak flow meter), and respiratory impedance (assessed with MostGraph®) were measured before and after a minimum of one year of Tio-Res 5 µg/day administration. Sixteen symptomatic, never-smoking asthmatics, aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA, were analyzed. All patients were female (mean age, 81.6 years). Tio-Res led to statistically significant improvements in the total ACT score (19.9 to 23.6), FVC and FEV1 (1.97 to 2.14 L and 1.13 to 1.23 L, respectively), and mPEF and ePEF (229.9 to 253.8 L/min and 259.8 to 277.4 L/min, respectively). Tio-Res also resulted in statistically significant improvements in respiratory resistance at 5 Hz (R5), respiratory resistance at 20 Hz (R20), R5-R20, low-frequency reactant indices at 5 Hz (X5), resonant frequency (Fres) and low-frequency reactance area (ALX). Our retrospective study suggests that Tio-Res improves symptoms, pulmonary function, and respiratory impedance in symptomatic asthmatics aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA.

Comparative Effectiveness of Two Tiotropium Formulations: A Retrospective Cohort Study

The effectiveness of the tiotropium Respimat® formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat® (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat® and HandiHaler®. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler® or Respimat®) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat® and HandiHaler® users were identified (adjusted hazard ratio 0.95, 95% CI 0.84–1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.

Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World: A TIOSPIR® Post-Hoc Analysis

IntroductionGeographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial. MethodsTIOSPIR®, a 2–3-year, randomized, double-blind trial (n=17116; treated set), compared safety and efficacy of once-daily tiotropium Respimat® 5 and 2.5μg with tiotropium HandiHaler® 18μg. This post-hoc analysis pooled data from all treatment arms to assess mortality, exacerbations, cardiac events, and serious adverse events (SAEs) between both regions. ResultsAt baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24–1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18–1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68–0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72–0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48–0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71–1.40]; P=.9677). ConclusionsTIOSPIR® patients in Latin America had a higher risk of death or moderate-to-severe exacerbation, but a lower risk of severe exacerbation than those in RoW. Geographical differences may impact outcomes in COPD trials.

Efficacy of once-daily tiotropium Respimat® in adults with asthma based on GINA steps 2 – 5

Efficacy of once-daily tiotropium Respimat® in adults with asthma based on GINA steps 2 – 5

Efficacy of Once-Daily Tiotropium Respimat® on Lung Function and Asthma Control in Adults with Asthma at GINA Steps 2–5

Efficacy of Once-Daily Tiotropium Respimat® on Lung Function and Asthma Control in Adults with Asthma at GINA Steps 2–5

Efficacy and Safety of Tiotropium in Children and Adolescents.

Asthma is one of the most common chronic diseases in children, with a high proportion of patients demonstrating poor control despite the availability of disease management guidelines. Global Initiative for Asthma guidelines include tiotropium as an add-on therapy option at Steps 4 and 5 in patients aged ≥ 12 years with a history of exacerbations, and tiotropium delivered via the Respimat® Soft Mist™ Inhaler has recently been approved for use as once-daily maintenance therapy for children with asthma over the age of 6 years in the USA. A large clinical trial program has been conducted in children, adolescents, and adults across the spectrum of asthma severity. Findings from these clinical studies and pooled analyses in children and adolescents with symptomatic moderate or severe asthma have demonstrated that tiotropium Respimat® as add-on to inhaled corticosteroids, with or without other maintenance therapies, is a well-tolerated and efficacious bronchodilator, showing improved lung function and trends towards improved asthma control, mirroring findings in adult studies. This review discusses the evidence to date for tiotropium Respimat® for the management of asthma in adolescents and children with symptomatic moderate and severe asthma, and considers the challenges of asthma management in these patients. Factors affecting this population group, such as poor adherence, underreporting of symptoms, and social and psychological issues, are highlighted, along with the need for active review and management of treatment to help achieve optimal control.

Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World: A TIOSPIR® Post-Hoc Analysis

IntroductionGeographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial. MethodsTIOSPIR®, a 2–3-year, randomized, double-blind trial (n=17116; treated set), compared safety and efficacy of once-daily tiotropium Respimat® 5 and 2.5μg with tiotropium HandiHaler® 18μg. This post-hoc analysis pooled data from all treatment arms to assess mortality, exacerbations, cardiac events, and serious adverse events (SAEs) between both regions. ResultsAt baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24–1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18–1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68–0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72–0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48–0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71–1.40]; P=.9677). ConclusionsTIOSPIR® patients in Latin America had a higher risk of death or moderate-to-severe exacerbation, but a lower risk of severe exacerbation than those in RoW. Geographical differences may impact outcomes in COPD trials.

Safety and Efficacy of Tiotropium Respimat® Add-on Therapy in Pre-school Children with Symptomatic Persistent Asthma

Purpose: Asthma is the most common chronic disease of childhood (GINA. Diagnosis and management of asthma in children 5 years and younger. 2015). The preferred controller medication in children aged ≤5 years is a low dose of inhaled corticosteroids (ICS). However, treatment options for these patients are limited if their asthma symptoms are not then well controlled on ICS. The aim of this study was to evaluate the safety and efficacy of once-daily tiotropium Respimat® in patients aged 1-5 years with symptomatic persistent asthma, as add-on to ICS with or without further maintenance therapy. Methods: A Phase II/III, randomized, double-blind, placebo-controlled, parallel-group trial (NCT01634113) in patients aged 1-5 years with symptomatic persistent asthma. Patients received tiotropium 5 µg (two puffs of 2.5 µg), tiotropium 2.5 µg (two puffs of 1.25 µg), or placebo (two puffs), administered once daily in the afternoon for 12 weeks via the Respimat® device, each as add-on to usual maintenance therapy of ICS with or without other controller medication. The primary objective was to determine the safety of tiotropium Respimat®. Safety data included post hoc analyses of three composite exacerbation endpoints derived from adverse events (AEs), with treatment comparisons reported as hazard ratios (95% confidence interval [HR (95% CI)]). The primary efficacy endpoint was change in the weekly mean combined daytime asthma symptom score from baseline at Week 12 (response). The co-primary endpoint in 5-year-olds was peak forced expiratory volume in 1 second within 3 hours post-dose (peak FEV1(0-3h)) response. Treatment comparisons for efficacy endpoints were exploratory, and no formal hypothesis testing was performed. Results: Of the 102 patients randomized, 101 were treated and completed the 12-week treatment period: tiotropium 5 µg, n=31; tiotropium 2.5 µg, n=36; placebo, n=34. Safety results were comparable between all treatment groups, with a lower proportion of patients reporting any AEs in the tiotropium groups (5 µg: 58.1%; 2.5 µg: 55.6%) than in the placebo group (73.5%). No AEs leading to treatment discontinuation or death were reported, and AEs were of mild or moderate intensity. Serious AEs were reported in three patients (8.8%), all in the placebo group. In post hoc analyses, both tiotropium doses reduced the risk of asthmatic exacerbation over 12 weeks compared with placebo (e.g. see exacerbation [broad] with pneumonia plus worsening in the figure). Tiotropium and placebo were associated with comparable improvements in weekly mean combined daytime asthma symptom score and peak FEV1(0-3h) responses (exploratory analyses); treatment comparisons were not performed for peak FEV1(0-3h) response because of insufficient patient numbers in each treatment group. Conclusion: Once-daily tiotropium Respimat® add-on to ICS with or without further maintenance therapy is safe and well tolerated, and may reduce exacerbations in pre-school children with symptomatic persistent asthma.