Tiotropium Group Research Articles

Anti-inflammatory effects of tiotropium in copd: a randomized double-blind trial

IntroductionChronic Obstructive Pulmonary Disease (COPD) is a major global health issue characterized by respiratory symptoms and exacerbations, significantly impacting mortality and quality of life. Muscarinic antagonists are known to prevent exacerbations, possibly by mitigating airway inflammation. This study evaluated the anti-inflammatory effects of tiotropium in patients with COPD by examining inflammatory protein profiles in sputum and blood, and genome-wide expression in sputum.MethodsWe conducted the prospective, double-blind, randomized-controlled ANTIOFLAM trial. Patients with COPD GOLD II and worse, aged≥40 years and with≥10 smoking pack years were included. After a 4-week wash-out period of inhaled corticosteroids (ICS) and anticholinergics, participants were randomized to 6 weeks of treatment with placebo or tiotropium (soft mist inhaler, 5 µg daily). Our primary endpoint was a decrease of sputum interleukin-6 and interleukin-8 levels in the tiotropium group when compared to the placebo group.ResultsWe evaluated samples of 33 participants (n=17 placebo and n=16 tiotropium). Changes in sputum proteins interleukin-6 and interleukin-8 were significantly higher after treatment with tiotropium when compared to placebo (p<0.05). Differential expression analysis did not reveal gene expression differences including interleukin-6 and −8.ConclusionWe did not find tiotropium to have anti-inflammatory effects in sputum or blood of patients with COPD. In contrast, we found 6 weeks of treatment with tiotropium to increase the concentration of almost all tested sputum inflammatory proteins when compared to placebo, while RNA expression levels did not change.

A comparative study on safety profile and efficacy of salmeterol and tiotropium in COPD Patients

Aim and Objectives: The aim of the study is assess the safety profile and efficacy of salmeterol and Tiotropium in patients with COPD. The objective is to compare to evaluate the safety profile and efficacy of salmeterol and Tiotropium in patients with COPD. Methodology: This was a prospective observational study conducted at secondary care hospital in India. In our study, we have included a total of 50 patients who are divided in to two groups based on their treatment and follow-ups was done for 12 weeks. Results: Patients were divided into 2 equal groups to receive salmeterol and Tiotropium (25 subjects each). The mean FEV1 level at baseline was 63.72±3.0210 for Tiotropium group and 64.96±1.645 for Salmeterol group and the mean FEV1 level after 12 weeks of treatment was 72.12±1.423 for Tiotropium group and 70.68±1.973 for Salmeterol group. Tiotropium treatment were associated with significant decrease in FEV1 level from baseline to 12 weeks. (P*<0.05). Conclusion: In our study, by performing the study, we concluded that tiotropium used once daily, produced superior bronchodilation and reduced dyspnea in patients with COPD when compared with salmeterol. Patients treated with tiotropium also indicated more improvement in their symptoms than those who treated with salmeterol. Because of these advantages, tiotropium should be considered first-line treatment in patients with COPD. While performing the safety parameters for a drug, side effects of tiotropium are less when compared to salmeterol.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial

BackgroundWe previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). ObjectiveWe sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. MethodsA total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 μg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. ResultsA total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. ConclusionTiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. Trial RegistrationClinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Tiotropium in Patients with Bronchiectasis: A Prospective Cohort Study.

There are limited studies on the use of bronchodilators for the treatment of bronchiectasis. This study investigated the efficacy of tiotropium in patients with bronchiectasis and airflow limitation. This study was a prospective cohort study, including 169 patients with bronchiectasis and airflow limitation from 2015 to 2019. The clinical outcomes observed in our study were the effect of tiotropium on the frequency of moderate exacerbations, the time to the first severe exacerbation, and the annual decline in FEV1. After 12months, the annual decline in the FEV1 after bronchodilator use was 27.08ml or 42.9ml per year in the group with or without tiotropium, respectively. Treatment with tiotropium was associated with a decreased risk of moderate exacerbation of bronchiectasis (Adjusted RR 0.618 95% CI 0.493-0.774; P < 0.005). The time to the first severe acute exacerbation of bronchiectasis in the tiotropium group was longer than the non-tiotropium group (Adjusted HR 0.333 95% CI 0.219-0.506; P < 0.001). In conclusion, prospective cohort study showed that tiotropium effectively ameliorated the annual decline in the FEV1, with a lower-risk rate of moderate exacerbations and prolonging the time to the first-time severe exacerbation in patients with bronchiectasis and airflow limitation.

Intermittent Tiotropium for Episodic Wheezing.

Approximately one third of children experience an episode of wheezing during the first 3 years of life, and nearly half of these children have recurrent wheezing episodes.1–3In spite of the substantial morbidity associated with this common condition, the optimal approach to management of acute wheezing episodes in young children is not known. Although short-acting β agonists and corticosteroids are frequently used, the effects of these medications in children younger than 3 years of age are less predictable than in school-aged children and adolescents.4 In addition, inhaled and systemic corticosteroids can be associated with harms, so effective corticosteroid-sparing therapies may be preferable.5,6Tiotropium, a selective long-acting anticholinergic agent, has been studied in older children and adults, mostly as adjunctive therapy in patients with moderate-to-severe asthma.7–12 Although not rigorously studied in young children, its anticholinergic mechanism of action offers potential benefits over—or in addition to—β agonists and corticosteroids by simultaneously promoting bronchodilation and preventing mucous secretion.In this issue of Pediatrics, Kotaniemi-Syrjänen et al report results from a randomized, open-label, controlled study of intermittent tiotropium for recurrent acute wheezing episodes in 80 children ages 6 to 35 months.13 Participants with 2 to 4 prior episodes of wheezing were randomized to receive either (1) tiotropium 5 µg once daily for 7 to 14 days, (2) fluticasone 125 µg twice daily for 7 to 14 days, or (3) albuterol 0.2 mg as needed 4 to 6 times daily, each at the onset of an acute respiratory tract infection. Participants in the tiotropium and fluticasone groups also used albuterol as needed. The primary outcome was the proportion of symptom-free days during the 48-week follow-up period, and secondary outcomes were the number of albuterol doses used and the number of adverse events requiring medical attention.Although recruitment was terminated early because of financial, logistical, and ethical reasons, the investigators found that treatment with tiotropium was associated with a greater proportion of symptom-free days (97%) compared with fluticasone (87%) or as-needed albuterol (88%). The differences in the primary outcome between the tiotropium group and the fluticasone and albuterol groups remained statistically significant after a 2-way factorial analysis of variance, accounting for baseline differences across groups. Because the distribution of the number of illness episodes was similar across study groups, the measured effect of tiotropium was attributed to less severe symptoms during illness episodes rather than to less frequent occurrence of illness. Patients in the tiotropium group used albuterol less frequently during illness episodes than those in fluticasone or albuterol groups, and all treatments were found to be safe.The investigators acknowledge important limitations of the study, including the small sample size, which—although not sufficiently small to obscure a difference in the main outcome measure across study groups—limited the study’s power to detect differences in rarer outcomes and may have contributed to imbalances in important baseline characteristics across groups. In addition, the lack of blinding may have led to biased measurement of treatment effects, particularly since the primary outcome was a parent-reported symptom score rather than an objective measure of lung function. Finally, some of the included patients who were less than 24 months of age may have had viral bronchiolitis, for which routine pharmacologic treatment has not been shown to be effective.14Despite these limitations, the investigators deserve praise for conducting an important exploratory study. Their results support prior findings that tiotropium is likely safe in young children15 and provide preliminary evidence that its intermittent use during respiratory tract infections could improve symptoms. If replicated in larger blinded studies, these results suggest that intermittent tiotropium use could prevent, on average, approximately 5 weeks of symptoms per year in young children with recurrent wheezing.This study also highlights the importance of ongoing work to define clinically useful phenotypes in young children with recurrent wheezing episodes. Existing classification systems define wheezing phenotypes according to epidemiologic characteristics, symptoms over time, genetics, and environmental factors.3,4,16–23 Although some of these tools have proven helpful to predict a future diagnosis of asthma, young children may express different phenotypes over time, and whether specific treatments are more effective among patients with different phenotypes is uncertain. In this way, studying the problem through the lens of precision medicine may help to better define which patients with wheezing are most likely to benefit from specific therapies.

Factors Associated with Reduction of Sedentary Time Following Tiotropium/Olodaterol Therapy in Treatment-Naïve Chronic Obstructive Pulmonary Disease

BackgroundProlonged sedentary behavior is associated with worse prognosis in patients with chronic obstructive pulmonary disease (COPD). Our previous study found that first-line dual therapy with tiotropium/olodaterol significantly reduces sedentary time compared to tiotropium monotherapy in Japanese patients with treatment-naïve COPD, although the characteristics of responders to dual-therapy versus monotherapy for COPD are still unclear.MethodsPatients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Physical activity was assessed using a triaxle accelerometer for 2 weeks before and after treatment. This analysis focused on the change in sedentary time, indicated by physical activity of 1.0–1.5 metabolic equivalents (METs), with stratification for the following factors: age, body mass index (BMI), pulmonary function, COPD assessment test (CAT), the 6-minute walk distance (6MWD), and physical activity level at study entry.ResultsThirty-five patients received tiotropium/olodaterol and 34 patients received tiotropium. In patients with lower inspiratory capacity at study entry, a significant reduction in sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: −12.8 ± 13.5 min, Tio/Olo: −65.1 ± 21.0 min, mean difference, −52.2 min, 95% CI −103.6 to 0.88, p = 0.046). In patients with a shorter duration of physical activity of ≥2 METs at study entry, a significant reduction of sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: −3.3 ± 17.5 min, Tio/Olo: −72.9 ± 23.1 min, mean difference, −69.7 min, 95% CI −128.7 to −10.6, p = 0.02). There were no differences in terms of age, BMI, CAT score, 6MWD, FEV1, FVC, VC, and physical activity of 1.0–1.5 METs and ≥3.0 METs.ConclusionThis study showed that COPD patients with lower inspiratory capacity or shorter active time of ≥2.0 METs at study entry are likely to exhibit significantly greater reduction in sedentary time with tiotropium/olodaterol treatment.

Low Dose Theophylline and Tiotropium Rotacap as Add on Therapy in COPD Patients-Clinical Trial

Objectives: To compare the role of low dose Theophylline and Tiotropium rotacap in improving the lung functions and day to day life of patients suffering from COPD. Study Design and Setting: A Clinical trial study was conducted at Department of Pharmacology and Therapeutics, BMSI in association with Department of Chest Medicine, JPMC. Methodology: This study was planned as an open label and parallel clinical trial study. A total of 168 patients of COPD were selected for this study and only 161 patients completed the 3 months duration of the study. The enrolled patients were grouped into 2, namely A and B. Tab. Theophylline 350 mg was given to Group A in two divided doses while Tiotropium rotacap18µg through rotahaler was given to group B once a day. Results: Mean FEV1 ± SD was improved by 0.04 ± 0.02 in Theophylline therapy group while by 0.07 ± 0.01 in the Tiotropium therapy treated group and a significant difference between the changes in the two treatment groups was evident. There was a percentage improvement in PEFR of 8.9 ± 5.8 in the Theophylline therapy treated group and of 13.2 ± 4.7 in Tiotropium therapy treated group. When Tiotropium group was compared with Theophylline group for improvement in percentage change in PEFR from day 0, a significant difference was evident between the two groups. There was a significant improvement from day 0 in CAT score in Tiotropium treated groups versus Theophylline group after 3 months of therapy. Conclusion: Tiotropium rotacap was more effective as compared to low dose Theophylline in improving pulmonary functions and CAT score in patients with COPD

Cost-Effectiveness of Tiotropium in Elderly Patients with Severe Asthma Using Real-World Data

Tiotropium has the potential to alleviate asthmatic symptoms caused by the aging of lungs. However, few studies have focused on specific treatments for elderly patients with asthma. To estimate the cost-effectiveness of adding tiotropium to inhaled corticosteroids and long-acting beta-agonists in elderly patients with severe asthma using real-world data. Phase I was a retrospective cohort study using the National Health Insurance claims data to measure clinical and economic outcomes. In phase II, a Markov model was constructed to evaluate cost-effectiveness from Korean health care system perspective, based on phase I, including 2 health states, and an asthma exacerbation event. We estimated cost given in 2018 US dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Subgroup analyses for patients with poorly controlled symptoms (frequent short-acting beta-agonist users; frequent exacerbators) were performed. In elderly patients with severe asthma, the incremental cost and effectiveness in the tiotropium group compared with the inhaled corticosteroid and long-acting beta-agonist group were $2281 and 0.038 QALYs, respectively. The incremental cost-effectiveness ratio was $60,074/QALY, indicating that the addition of tiotropium is not a cost-effective alternative. Meanwhile, 2 subgroups with poorly controlled symptoms showed that adding tiotropium is a cost-effective alternative (frequent short-acting beta-agonist users $4078/QALY; frequent exacerbators $8332/QALY). Tiotropium shows a higher cost-effectiveness profile when applied to elderly patients with uncontrolled symptoms. These results using real-world evidence provide information beyond the clinical outcomes reported by randomized controlled trials, providing a complementary ground in establishing the reimbursement criteria of tiotropium for elderly patients with severe asthma.

ENSIFENTRINE ADDED ON TO TIOTROPIUM SIGNIFICANTLY IMPROVES INSPIRATORY CAPACITY IN PATIENTS WITH SYMPTOMATIC COPD

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Ensifentrine (RPL554) is an investigational, first-in-class, inhaled dual inhibitor of PDE3 and PDE4 that combines bronchodilator and anti-inflammatory actions in a single compound. In a previously completed dose-ranging study in patients with COPD, nebulized ensifentrine delivered clinically meaningful and significant improvements versus placebo in lung function and symptoms (Singh et al. 2020). In a second dose-ranging study, nebulized ensifentrine (0.375, 0.75, 1.5 or 3 mg) or placebo was given in addition to tiotropium for 4 weeks in symptomatic COPD patients following a 14-day run-in on tiotropium. All ensifentrine doses produced significant bronchodilation on top of tiotropium with a dose-dependent increase from baseline to peak FEV1 (primary endpoint) at week 4 of 78 to 124 mL (placebo-corrected; all p<0.05). This abstract reports on the pre-specified exploratory investigation of the effect of twice-daily nebulized ensifentrine versus placebo on inspiratory capacity (IC) in the same study. METHODS: Analysis was performed on all randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters based on FEV1 on at least one occasion. The analysis comprised 413 patients with 83, 83, 81, 82 in the 0.375, 0.75, 1.5, 3.0 mg ensifentrine + tiotropium groups and 84 in the placebo + tiotropium treatment group. IC maneuvers were conducted according to ATS/ERS guidelines (Miller et al, 2005) prior to the forced maneuvers 30 minutes pre-dose and 2 hours post-dose following randomization (Day 1) and at the last dose at Week 4. The change from baseline was calculated. RESULTS: Mean age was 64.3 years, with 52.2% under 65 years of age. Patients were primarily female (57.5%), caucasian (90.1%) and current smokers (55.3%) with chronic bronchitis (59%). Day 1 baseline IC was similar between treatment groups. Placebo-corrected change from baseline in IC on Day 1 (2h post-dose) was 76, 62, 115 and 108 mL for the 0.375, 0.75, 1.5, 3.0 mg ensifentrine + tiotropium groups, respectively. The 1.5 and 3 mg doses showed statistically significant improvements (p<0.01). After 4 weeks of twice-daily ensifentrine added to once daily tiotropium, there was a statistically significant improvement of 110.2 mL in IC (2 h post-dose) compared with placebo (tiotropium alone, p=0.0290) with the 3 mg ensifentrine dose + tiotropium treatment group. CONCLUSIONS: This study demonstrates a clinically meaningful response in IC after treatment with 4 weeks of ensifentrine in COPD patients who remain symptomatic and with impaired lung function despite the use of tiotropium. CLINICAL IMPLICATIONS: Measurement of IC as a marker of dynamic lung hyperinflation has been shown to correlate with dyspnea and exercise performance in stable COPD. Results suggest a physiological mechanism by which ensifentrine improved symptoms and health-related quality of life. DISCLOSURES: Consultant relationship with Verona Pharma Please note: $5001 - $20000 Added 06/01/2020 by Thomas Bengtsson, source=Web Response, value=Consulting fee Employee relationship with Verona pharma Please note: >$100000 by Tara Rheault, source=Admin input, value=Stock Employee relationship with Verona Pharma Please note: >$100000 Added 05/20/2020 by Kathleen Rickard, source=Web Response, value=Salary

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.

Tiotropium (SPIRIVA®) in mild COPD: Is it worth it?

Purpose:Tiotropium (SPIRIVA®) is used in the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in patients with persistent dyspnea despite using a short acting bronchodilator (SABD).This paper explores the role of tiotropium in the treatment of mild COPD. Methods:The Cochrane Library, EMBASE, Pubmed, and Clinicaltrials.gov were searched on February 2018.We included randomized controlled trials (RCTs) that evaluated tiotropium in patients with mild COPD.Three authors assessed studies for eligibility. Outcomes included symptoms, quality of life, exercise duration, lung function, COPD exacerbations and hospitalizations, and serious adverse events. Results: Three RCTs were selected as the best available evidence. Based on the results of the main trial, quality of life and symptoms were improved with tiotropium as compared to placebo with a difference between groups at 24 months to be 1.2 (95% CI: 0.5 to 1.9; p=0.0011) using the COPD Assessment test (CAT) score. Frequency of acute exacerbations of COPD (AECOPD) requiring hospitalization was reduced by 10.3% (28.9% with tiotropium vs 39.2% with placebo) in patients receiving tiotropium. One RCT reported no statistically significant difference in exercise duration (27 ± 27 secs) in the tiotropium group vs 50 ± 21 secs in the placebo group; (p=0.4153). Oropharyngeal discomfort was more common with tiotropium (number needed to harm of 12) compared to placebo. Conclusions: Evidence suggests that tiotropium may reduce COPD exacerbations and hospitalizations and improve quality of life in patients with mild COPD.There is an increased risk of oropharyngeal discomfort with tiotropium.

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.

Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 μg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 μg (n = 23, 5.6%) and revefenacin 175 μg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 μg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 μg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 μg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.

Effect of tiotropium inhaler use on mortality in patients with tuberculous destroyed lung: based on linkage between hospital and nationwide health insurance claims data in South Korea

BackgroundAlthough bronchodilator inhaler therapy can improve lung function in patients with tuberculous destroyed lung (TDL), its effect on mortality has not been studied. We evaluated the effect of tiotropium inhaler therapy on mortality in patients with TDL.MethodsA retrospective cohort of 963 patients with TDL was followed for up to ten years by linking hospital and nationwide health insurance claims data. We compared patients receiving tiotropium inhaler with patients without tiotropium after matching with propensity scores. In addition, we elucidated the risk factors of mortality using Cox proportional hazards model.ResultsAfter the propensity score matching, the baseline characteristics were balanced in both the tiotropium group (n = 105) and the non-tiotropium group (n = 105); including mean age (63.9 vs. 64.4 years, P = 0.715), mean forced expiratory volume in 1 s (FEV1) (45.0 vs. 45.3%, P = 0.903), and others. After the propensity score matching, the tiotropium group showed better survival than the non-tiotropium group (median survival period: not reached for the tiotropium group vs. 7.24 years for the non-tiotropium group, Prentice-Wilcoxon test, P = 0.008). Multivariate Cox proportional hazard analysis revealed that tiotropium inhaler usage was associated with lower risk of mortality in the multivariate analysis (HR, 0.560; 95% CI, 0.380–0.824; P = 0.003) after adjusting age, sex, BMI, smoking history, mMRC dyspnea score, Charlson Comorbidity Index, concomitant COPD diagnosis, FEV1, X-ray severity score, and home oxygen usage.ConclusionsOur results suggest that tiotropium inhaler is associated with decreased all-cause mortality in TDL. Further prospective study is required for validation.

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.

CARDIOVASCULAR SAFETY OF REVEFENACIN FOR NEBULIZATION: A REVIEW OF RANDOMIZED CONTROLLED TRIAL DATA

SESSION TITLE: Obstructive Lung Diseases 2 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Revefenacin, a once-daily, lung-selective, long-acting muscarinic receptor antagonist in clinical development for the nebulized treatment of chronic obstructive pulmonary disease (COPD), produces sustained bronchodilation with limited systemic adverse events (AEs). As cardiovascular (CV) disease is highly prevalent in COPD patients, we evaluated CV safety data from 3 randomized trials of revefenacin, and a thorough QT study in healthy subjects. METHODS: CV safety data were assessed in a phase 1, placebo- and positive-controlled thorough QT study in healthy subjects receiving therapeutic (175 μg) and supratherapeutic (700 μg) inhaled single doses of revefenacin (Study 0136, N=48). The potential association between daily nebulized revefenacin 88 μg and 175 μg and CV safety was evaluated in patients with moderate to very severe COPD in 2 identical, 12-week, placebo-controlled, phase 3 trials (Study 0126, N=619; Study 0127, N=611), and an active-controlled, 52-week, phase 3 safety trial (Study 0128, N=699). An independent external clinical events committee (CEC) performed blinded review and adjudication of all prespecified major CV AEs (MACE) in studies evaluating COPD patients. RESULTS: Single doses of revefenacin did not have a clinically meaningful effect on cardiac repolarization (QTcF) in healthy subjects. No clinically meaningful changes in 12-lead ECG recordings were observed with up to 52 weeks of daily revefenacin 88 μg and 175 μg in patients with COPD. The incidences of prolonged QTcF interval (>450 msec) were similar in the placebo (4.9% and 5.8%), revefenacin 88 μg (6.3% and 4.9%) and revefenacin 175 μg (5.1% and 6.7%) arms of Studies 0126 and 0127, respectively. In Study 0128, the incidences of prolonged QTcF were similar in the revefenacin 175 μg (7.7%) and tiotropium (7.3%) groups, and slightly lower in the revefenacin 88 μg group (4.2%). No CV-related treatment-emergent AEs were reported with single-dose revefenacin at doses of 175 μg and 700 μg in healthy subjects. After CEC adjudication, there were 4 MACE in Study 0126 (2, 1, and 1 in the revefenacin 88 μg, revefenacin 175 μg, and placebo groups, respectively), zero MACE in Study 0127, and 26 MACE in Study 0128 (9, 10, and 7 in the revefenacin 88 μg, revefenacin 175 μg, and tiotropium groups, respectively). Only 1 of these MACE was considered related to revefenacin (atrial fibrillation in the revefenacin 175 μg group in Study 0128). CONCLUSIONS: Revefenacin for nebulization does not prolong QT interval. No increased risk of MACE was identified in clinical trials up to 52 weeks in duration. CLINICAL IMPLICATIONS: Once-daily revefenacin over periods of up to 1 year is associated with acceptable CV safety and, thus, may provide beneficial nebulized therapy for patients with COPD. DISCLOSURES: No relevant relationships by Chris Barnes, source=Web Response Consultant relationship with Theravance Biopharma Please note: >$100000 Added 03/09/2018 by Marie Borin, source=Web Response, value=Consulting fee Employee relationship with Theravance Biopharma Please note: >$100000 Added 03/08/2018 by David Bourdet, source=Web Response, value=Salary No relevant relationships by Borje Darpo, source=Web Response Advisory Committee Member relationship with Mylan Inc Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Honoraria Removed 03/02/2018 by James Donohue, source=Web Response Advisory Committee Member relationship with Sunovion Pharmaceuticals Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Mylan Inc Please note: $1001 - $5000 Added 03/02/2018 by James Donohue, source=Web Response, value=Consulting fee No relevant relationships by Gregory Feldman, source=Admin input Employee relationship with Theravance Please note: >$100000 Added 03/02/2018 by Srikanth Pendyala, source=Web Response, value=Salary Research funds to institution relationship with Astra Zeneca Please note: $20001 - $100000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Astra Zeneca Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Boerhinger Ingelheim Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Honoraria Advisory Committee Member relationship with Boerhinger Ingelheim Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Glaxo Smith Kline Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Clinical Event adjudication committee relationship with Pulmonx Please note: $5001 - $20000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Sunovion Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Theravance Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Circassia Please note: $1001 - $5000 Added 03/09/2018 by Sanjay Sethi, source=Web Response, value=Consulting fee

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George’s Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.

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.

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.

Влияние на парадигму предупреждения обострений хронической обструктивной болезни легких фиксированной комбинации Тиотропий / Олодатерол

Chronic obstructive pulmonary disease (COPD) has a varying frequency and severity of exacer-bations. The fixed combination of tiotropium / olodaterol (TIO/OLO) demonstrate a reduction of risk moderate and severe exacerbations compare to tiotropium (TIO) in patients with COPD. Ti-otropium-olodaterol reduced the rate of exacerbations treated with systemic corticosteroids (SCS) alone, and reduced the rate of exacerbations treated with SCS and antibiotics compared with tiotropium.. There was no difference in the number of adverse events including major ad - verse cardiac events between TIO/OLO and tiotropium groups.