Safety Of Tiotropium Research Articles

Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT.

RationaleThere is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear.ObjectivesTo examine the relationship between BMI and adverse outcomes in COPD.MethodsThis post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m2], normal weight [BMI 20 to <25 kg/m2], overweight [BMI 25 to <30 kg/m2], obesity class I [BMI 30 to <35 kg/m2], obesity class II [BMI 35 to <40 kg/m2], and obesity class III [BMI ⩾ 40 kg/m2]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models.ResultsIn TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62–2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16–1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR.ConclusionsThese results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD.

Evidencia de Tiotropio en asma.

Asthma is a chronic disease with a significant disease burden and many patients fail to control the disease despite recommended medical therapy.19 The long-term goals of asthma management include achieving good control of symptoms, minimizing risk asthma exacerbations, reduce hospitalizations, use of rescue medication, airflow limitation and side effects, as well as allow normal levels of activity.29 According to the Global Initiative for Asthma (GINA) guidelines , asthma management is based on a cornerstone of inhaled corticosteroid therapy (ICS), supplemented with complementary therapies for those with poor or deteriorating disease control.1 Tiotropium, a long-acting anticholinergic bronchodilator that is administered once a day, it is indicated for the treatment of chronic obstructive pulmonary disease (COPD) for more than a decade and has recently been approved in several countries for the treatment of asthma.18 In this review, we summarized the significant effect of tiotropium for the treatment of moderate-to-severe asthma, mainly in increasing morning PEF, evening PEF, peak FEV and trough FEV based on high-quality RCTs. Nevertheless, no significant difference in peak FVC, trough FVC, AE and serious AE was found between the 2 groups. A close comparison of the 2 groups revealed that more high-quality larger-sample RCTs are needed to gather more strong evidence on the therapeutic efficacy and safety of tiotropium for clinical practice.

Tiotropium: efficacy and safety in pediatric bronchial asthma

Bronchial asthma is one of the most common chronic lung diseases observed in children. According to the international and Russian guidelines, the long-term objectives of asthma treatment in children and adolescents are to achieve good symptom control, minimize the risk of asthma exacerbations, reduce hospital admissions, decrease the use of short-acting bronchodilators, reduce restrictions in the airflow and side effects, and ensure that normal activity levels are maintained. The asthma treatment is based on the use of inhaled corticosteroids as a backbone therapy and addition of adjunctive therapy if the disease control is poor or worsening. Tiotropium bromide is the first anticholinergic drug that has been approved for children and adults with poorly controlled asthma and is currently used as a treatment option for moderate to severe bronchial asthma. Randomized clinical trials in children and adolescents with persistent bronchial asthma showed high efficacy and safety of tiotropium. The addition of tiotropium in the form of 2 inhalations of 2.5 μg once a day to the bronchial asthma therapy in children over 6 years old, including medium doses of inhaled corticosteroids, is a preferred and safe option to increase the therapy coverage compared to an increase of a dose of inhaled corticosteroids to high levels, regardless of the disease phenotype (In atopic, non-atopic bronchial asthma, bronchial asthma with obesity, etc.). Tiotropium adjunctive therapy may also be a therapeutic option for children using inhaled corticosteroids, who have asthma that does not respond well to long-acting β2-agonist therapy, or for those, who are worried about the safety of long-acting β2-agonists.

Tiotropium in Children and Adolescents With Asthma

KR Murphy, BE Chipps. Ann Allergy Asthma Immunol . 2020;124(3):267–276.e3 To perform a systematic review of published data to evaluate the efficacy and safety of tiotropium, a long-acting muscarinic antagonist (LAMA), as an add-on therapy in children and adolescents with uncontrolled asthma currently on inhaled corticosteroid (ICS) maintenance therapy with or without other controller medications. The systematic review included randomized controlled trials (RCTs) of patients aged 1 to 17 years treated with once daily tiotropium (5µg, 2.5µg, or 1.25 µg administered via slow/soft mist inhaler Respimat) as add on therapy to ICS for 12 or …

Severe asthma: adding new evidence – Latin American Thoracic Society

This document constitutes a summary of the clinical practice guidelines (CPGs) prepared at the initiative of the Latin American Thoracic Society (ALAT). Due to new evidence in the treatment of severe asthma, it was agreed to select six clinical questions, and the corresponding recommendations are provided herein. After considering the quality of the evidence, the balance between desirable and undesirable impacts and the feasibility and acceptance of procedures, the following recommendations were established. 1) We do not recommend the use of an inhaled corticosteroid (ICS) plus formoterol as rescue medication in the treatment of severe asthma. 2) We suggest performing many more high-quality randomised studies to evaluate the efficacy and safety of tiotropium in patients with severe asthma. 3) Omalizumab is recommended in patients with severe uncontrolled allergic asthma with serum IgE levels above 30 IU. 4) Anti-interleukin (IL)-5 drugs are recommended in patients with severe uncontrolled eosinophilic asthma (cut-off values above 150 cells·µL−1 for mepolizumab and above 400 cells·µL−1 for reslizumab). 5) Benralizumab is recommended in adult patients with severe uncontrolled eosinophilic asthma (cut-off values above 300 cells·µL−1). 6) Dupilumab is recommended in adult patients with severe uncontrolled allergic and eosinophilic asthma and in adult patients with severe corticosteroid-dependent asthma.

Efficacy and Safety of Inhaled Indacaterol and Tiotropium in Patients of Chronic Obstructive Pulmonary Disease

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide. Indacaterol is a new once daily inhaled bronchodilator, recently approved for the treatment of COPD. Once daily dosing is an important step to improve the adherence and compliance of the patients. Methods: Efficacy and Safety of Indacaterol and Tiotropium in Patients of COPD with Stage-2 and Stage-3 GOLD criteria were compared. Total 119 patients were divided into Indacaterol group and Tiotropium group receiving 150 mcg daily of Indacaterol and 18 mcg daily of Tiotropium in each group respectively. Efficacy treatment was determined by assessment of Pulmonary function test (PFT), Symptom score and SGRQ (St. George’s Respiratory Questionnaires) score at day zero (before therapeutic intervention) and at two weeks of interval till 24 weeks. Results: The treatment with inhaled indacaterol 150 mcg once daily and inhaled tiotropium 18 mcg once daily improved spirometric variable, FEV1, decrease in mean Symptoms score and in mean SGRQ in Grade-2 and Grade-3 COPD patients. Conclusion: Indacaterol (150 mcg/day) is non-inferior to tiotropium (18 mcg /day) in efficacy and safety profile of Grade-2 and Grade-3 patients with COPD.

Comparative Effectiveness and Safety of Tiotropium and Olodaterol in Comparison to Triple Therapy

Comparative Effectiveness and Safety of Tiotropium and Olodaterol in Comparison to Triple Therapy

Tiotropium in children and adolescents with asthma

BackgroundAsthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium—a long-acting muscarinic antagonist—as add-on therapy to an inhaled corticosteroid with or without a long-acting β2-agonist provides clinical benefit with a safety profile similar to placebo. ObjectiveTo review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s). MethodsWe searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events. ResultsOverall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 μg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection. ConclusionOnce-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.

Comparative Effectiveness and Safety of Tiotropium and Olodaterol in Comparison to LABA/ICS

Comparative Effectiveness and Safety of Tiotropium and Olodaterol in Comparison to LABA/ICS

Efficacy of tiotropium in treating patients with moderate-to-severe asthma: A meta-analysis and systematic review based on 14 randomized controlled trials.

Background:The goal of the current meta-analysis and systematic review was to explore the efficacy of tiotropium in treating patients with moderate-to-severe asthma on the basis of qualified randomized controlled trials (RCTs).Methods:The following online electronic databases, such as Cochrane, PubMed, and Embase database were screened to identify qualified studies updated to January 2019 through the use of index words. Several literatures that were relevant to the present analysis were also included. To further analyze the main outcomes, we utilized the odds rations (OR), and mean difference (MD) along with its 95% confidence interval (95% CI).Results:A total of 14 RCTs with 4998 patients in the tiotropium group and 5074 patients in the control group were included in the present study. On the basis of the pooled results, tiotropium was significantly associated with improved morning PEF (SMD: 3.29, 95%CI: 2.03–4.55), evening PEF (SMD: 3.36, 95%CI: 2.24–4.48), peak FEV (SMD: 2.67, 95%CI: 1.47–3.88), and trough FEV (SMD: 1.90, 95%CI: 0.87–2.92) vs the control group. Nevertheless, no significant difference was observed in peak FVC (SMD: 0.77, 95%CI: −0.21–1.76), trough FVC (SMD: 0.67, 95%CI: −0.18–1.53), AE (RR: 0.98, 95%CI: 0.94–1.02) and serious AE (RR: 1.08, 95%CI: 0.77–1.52) between the 2 groups.Conclusions:In this review, we summarized the significant effect of tiotropium for the treatment of moderate-to-severe asthma, mainly in increasing morning PEF, evening PEF, peak FEV and trough FEV based on high-quality RCTs. Nevertheless, no significant difference in peak FVC, trough FVC, AE and serious AE was found between the 2 groups. A close comparison of the 2 groups revealed that more high-quality larger-sample RCTs are needed to gather more strong evidence on the therapeutic efficacy and safety of tiotropium for clinical practice.

Add-on Tiotropium in Chinese Patients With Moderate Asthma: A Pooled Subgroup Analysis of MezzoTinA-Asthma 1 and 2.

PurposeAsthma affects approximately 30 million patients in China; however, tiotropium data for Chinese patients is limited. This study aimed to assess the efficacy and safety of tiotropium in Chinese patients with moderate symptomatic asthma.MethodsA post hoc subgroup analysis was conducted on 430 Chinese patients pooled from two 24-week, replicate phase 3 trials (NCT01172808 and NCT01172821), in which they received once-daily tiotropium 2.5 µg (Tio R2.5) or 5 µg (Tio R5) (n = 106 or 109, respectively), twice-daily salmeterol 50 µg (Sal 50) (n = 110), or placebo (n = 105), while maintaining inhaled corticosteroids (ICS). The co-primary endpoints assessed in week 24 were forced expiratory volume in 1 second (FEV1) peak0–3h response, trough FEV1 response, and responder rate as assessed using the Asthma Control Questionnaire (ACQ).ResultsFor both FEV1 peak0–3h responses and trough FEV1 responses, the mean treatment differences were greater for Tio R2.5, Tio R5, and Sal 50 compared with placebo at 0.249 L, 0.234 L, and 0.284 L, and 0.172 L, 0.180 L, and 0.164 L, respectively (P< 0.001). The ACQ responder rate in placebo, Tio R2.5, Tio R5, and Sal 50 was 58.7%, 62.3%, 59.3%, and 69.1%, respectively. Furthermore, 11 (2.6%) of 430 patients had serious adverse events (Tio R5, n = 4; Tio R2.5, n = 1; Sal 50, n = 1; and placebo, n = 5).ConclusionsOnce-daily tiotropium, as add-on to medium-dose ICS, was effective and well tolerated for Chinese patients with moderate symptomatic asthma, consistent with the main analysis.

Safety of tiotropium in patients with asthma.

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.

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.

The Effect of FDA Drug Safety Communications on Patterns of Tiotropium Dispensing: A U.S. Health Plan Claims Database Study.

The FDA issued 2 main drug safety communications (DSCs) on the cardiovascular safety of tiotropium in March 2008 (warning of a potential increased stroke risk) and January 2010 (informing of an absence of a significant increased stroke risk or cardiovascular events based on findings from a large trial). To describe the effect of the FDA DSCs on medication dispensing of tiotropium in a large U.S. claims database. Initiation of tiotropium products among patients with chronic obstructive pulmonary disease (COPD) aged 40 years and older was determined monthly from 2006-2012 using medication dispensing from the IMS Lifelink Health Plan Claims Database. Similarly, monthly initiation of products containing long-acting beta-agonists (LABAs) was calculated to explore product switching. The effect of the 2008 and 2010 FDA DSCs was measured using interrupted time-series analysis. Subgroups of patients with greater cardiovascular risk were also examined. A decreasing trend in initiation of tiotropium-containing products was present before the initial 2008 DSC. The decline in tiotropium initiation continued until January 2010, accompanied by an increased initiation of LABA-containing products in patients with COPD. In the presence of the existing decreasing trend, the initial DSC was followed by an immediate 2.8% (P = 0.02) further reduction in tiotropium initiation. Tiotropium initiation increased 2.5% (P = 0.03) immediately after the 2010 DSC, reducing the overall decline in rate and stabilizing (flattening) the trend. No significant changes in dispensing level or trend were observed among COPD patients with cardiovascular comorbidity. Cardiovascular safety concerns may have affected tiotropium initiation as indicated by the decrease in tiotropium dispensing shown immediately following the initial DSC. The effect was alleviated as concerns lessened following the most recent DSC. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are employed by the FDA and have no conflict of interest relevant to the content of this study. The views expressed herein do not necessarily represent the views of the FDA.

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.

Long-Term Safety of Tiotropium/Olodaterol Respimat in Patients with Moderate-to-Very Severe COPD and Renal Impairment in the TONADO Studies

Lung function, symptom benefits, and safety of combined tiotropium (T) and olodaterol (O) in the treatment of COPD were established in TONADO studies (NCT01431274; NCT01431287). As T is predominantly excreted by the kidneys, we investigated the long-term safety profile of T/O in patients with renal impairment (RI) in the TONADO studies.

Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR&lt;sup&gt;&amp;reg;&lt;/sup&gt; trial

BackgroundAlthough COPD exacerbations are known to occur more frequently in winter, there is little information on hospitalizations and cause-specific mortality. This study aimed to examine seasonal variations in mortality and exacerbations in patients with COPD during the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial.Patients and methodsTIOSPIR was a large-scale, multicenter trial, which assessed the safety and efficacy of tiotropium delivered via HandiHaler® (18 μg once daily) or Respimat® Soft Mist™ (2.5 or 5 μg once daily) inhaler in patients with COPD. Patients were aged ≥40 years, with a smoking history ≥10 pack-years, and post-bronchodilator forced expiratory volume in 1 second ≤70% and forced expiratory volume in 1 second/forced vital capacity ≤0.70. COPD exacerbations and deaths were monitored throughout the trial. The data were pooled to examine seasonal patterns. Southern hemisphere data were shifted by 6 months to align with northern hemisphere seasons.ResultsTIOSPIR was conducted in 43 northern (n=15,968) and 7 southern (n=1,148) hemisphere (n=1,148) countries. The median duration of treatment was 835 days, with a mean follow-up of 2.3 years. Among 19,494 exacerbations, there were clear seasonal differences (winter, 6,646 [34.1%]; spring, 4,515 [23.2%]; summer, 3,198 [16.4%]; autumn, 5,135 [26.3%]). Exacerbations peaked in early winter (December in the northern hemisphere and June in the southern hemisphere), respiratory hospitalizations in midwinter, and respiratory deaths in early spring.ConclusionAlthough winter poses a 2-fold hazard for COPD exacerbations vs summer, respiratory deaths peak in early spring. These data suggest that seasonal intensification of preventive treatments may impact COPD morbidity and mortality.Trial registration numberNCT01126437.

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.

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

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. 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. 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. 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. Boehringer Ingelheim.

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.