Tiotropium Respimat Research Articles

Tiotropium Respimat® in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials

BackgroundTiotropium Respimat® improved lung function in a phase 2 trial in patients with cystic fibrosis (CF). We investigated its efficacy and safety in a phase 3 trial, including a pre-specified pooled analysis of the phase 2 and 3 trials. Methods12-week, randomized, double-blind, placebo-controlled trial of tiotropium Respimat® 5μg once daily in patients with CF (N=463). ResultsCo-primary efficacy endpoints showed no statistical difference between tiotropium and placebo: percent-predicted forced expiratory volume in 1s (FEV1) area under the curve from 0–4h (AUC0–4h) (95% CI): 1.64% (0.27,3.55; p=0.092); percent-predicted trough FEV1 (95% CI) 1.40% (0.50,3.30; p=0.15). Adverse events were similar between groups. Pooled phase 2/3 trial results showed a treatment difference in favor of tiotropium: percent-predicted FEV1 AUC0–4h (95% CI): 2.62% (1.34,3.90). ConclusionTiotropium was well tolerated in patients with CF; lung function improvements compared with placebo were not statistically significant in the phase 3 trial. Clinical trialsThese studies are registered with clinical trial identifier numbers NCT00737100 and NCT01179347NCT00737100NCT01179347. These studies are also registered with the EudraCT number: 2008-001156-43 and 2010-019802-17.

Once-daily tiotropium Respimat® is well tolerated and efficacious over 52 weeks in Japanese patients with symptomatic asthma receiving inhaled corticosteroids (ICS)± long-acting β2-agonist (LABA): a randomized, double-blind, placebo-controlled study

Rationale: The present study evaluated long-term safety and efficacy of tiotropium Respimat® (tioR) in Japanese patients with moderate to severe symptomatic asthma, despite ICS ± LABA.

Exacerbator subtypes in the TIOtropium Safety and Performance In Respimat (TIOSPIR™) trial

Background: Cardiovascular (CV) comorbidities in chronic obstructive pulmonary disease (COPD) patients are frequent. We evaluated whether baseline variables can predict mortality and CV events in the TIOSPIR trial (17,116 COPD patients receiving tiotropium Respimat 5 or 2.5µg or HandiHaler 18µg for a mean of 2.3 yrs).

Once-daily tiotropium Respimat add-on to ICS ± LABA improves control across asthma severities

Background: Tiotropium Respimat added to ICS±LABA has been investigated across asthma severities. We present ACQ-7 responses from six Phase III randomised, double-blind, placebo-controlled, parallel-group trials in patients with symptomatic asthma.

Once-daily tiotropium Respimat add-on to at least ICS maintenance therapy reduces exacerbation risk in patients with uncontrolled symptomatic asthma

Once-daily tiotropium Respimat add-on to at least ICS maintenance therapy reduces exacerbation risk in patients with uncontrolled symptomatic asthma

Tiotropium HandiHaler(®) and Respimat(®) in COPD: a pooled safety analysis.

IntroductionTiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler® (18 μg once daily) or Respimat® Soft Mist™ inhaler (5 μg once daily). The recent TIOtropium Safety and Performance In Respimat® (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium® using data from placebo-controlled HandiHaler® and Respimat® trials.MethodsPooled analysis of adverse event (AE) data from tiotropium HandiHaler® 18 μg and Respimat® 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler® and Respimat® trials, both together and separately.ResultsIn the 28 HandiHaler® and 7 Respimat® trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler®; 2,440 with Respimat®) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler® and Respimat® pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.ConclusionThis analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler® or Respimat® (overall and separately) in patients with COPD.

Once-daily Tiotropium Respimat® Add-on to at Least ICS Maintenance Therapy Reduces Airflow Obstruction in Patients with Symptomatic Asthma, Independent of Allergic Status

A significant proportion of patients with asthma remain symptomatic despite treatment with ICS±LABA maintenance therapy. We investigated whether the efficacy of once-daily tiotropium Respimat®(tioR) add-on to at least ICS was influenced by allergic status in adult patients with varying severities of symptomatic asthma.

Tiotropium Respimat® Soft Mist™ inhaler: a guide to its use in chronic obstructive pulmonary disease (COPD) in the EU

Tiotropium Respimat® Soft Mist™ inhaler (Spiriva® Respimat®) is indicated as a maintenance bronchodilator to relieve the symptoms of patients with chronic obstructive pulmonary disease (COPD) in the EU. The delivered drug dose is independent of inspiratory effort and the prolonged duration of the aerosol cloud should make the co-ordination of actuation and inhalation easier. In patients with COPD, tiotropium Respimat® improved lung function, COPD exacerbations, health-related quality of life and dyspnoea, and was generally well tolerated. Relative to administration of tiotropium via the HandiHaler®, administration of the drug via the Respimat® Soft Mist™ inhaler improves lung deposition of the drug (allowing a lower nominal dose to be used), is at least as effective, and has a similar tolerability profile.

Consensus report: indications for use of long-acting antimuscarinic tiotropium in the treatment of bronchial asthma

Relevant indications for tiotropium Respimat in adult patients with bronchial asthma (BA) were reviewed. This consensus represents a collaborative effort of members of the Executive Group of Russian Respiratory Society. The Group consisted of clinicians, pharmacologists and researchers with recognized expertise in therapeutic field. The draft of the recommendations was prepared by initiative group. Each point of the recommendation was discussed during Executive group meeting and was accepted by vote of majority members. Final version of the consensus statement was approved by each member of Executive group. As concluded, tiotropium Respimat could be recommended for adult patients with bronchial asthma as: 1) add-on therapy in patients with severe and moderate severe non-controlled BA on GINA step 3–5 (ICS and LABA, including oral steroids or other controllers, or high doses ICS monotherapy); 2) add-on therapy in patients with asthma-COPD overlap syndrome (ACOS); 3) add-on therapy to ICS in case of side effects, contraindications for use or individual intolerance of LABA; 4) additional indications to consider use of tiotropium Respimat may include: smoking, positive SABA reversibility test, predominant nocturnal asthma symptoms.

Once-daily tiotropium Respimat® 5 μg is an efficacious 24-h bronchodilator in adults with symptomatic asthma

Once-daily tiotropium Respimat(®) 5 μg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting β2-agonists in patients with symptomatic asthma. The objective of this study was to investigate whether the dosing regimen of tiotropium (once- versus twice-daily), delivered via the Respimat(®) SoftMist™ inhaler, affected 24-h bronchodilator efficacy and safety versus placebo Respimat(®) in patients with asthma who were symptomatic despite medium-dose ICS therapy. A randomised, double-blind, placebo-controlled, crossover study with 4-week treatment periods of tiotropium 5 μg (once-daily, evening) and 2.5 μg (twice-daily, morning and evening). The primary efficacy end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC)(0-24h) at the end of each treatment period. Secondary end points included peak forced expiratory volume in 1 s measured within 24 h of the last evening inhalation (peak FEV1(0-24h)), trough FEV1 measured prior to evening dosing, morning and evening peak expiratory flow (PEFam and PEFpm) and pharmacokinetic assessments. 94 patients were randomised (mean age 44.3 years; mean asthma duration 21.3 years) and 89 (94.7%) completed the study. Significant and comparable bronchodilation was achieved over a 24-h period with both tiotropium dosing regimens. FEV1 AUC(0-24h) response (mean ± standard error) was significantly greater with both tiotropium dosing regimens (once-daily 5 μg: 158 ± 24 mL; twice-daily 2.5 μg; 149 ± 24 mL; both p < 0.01) when compared with placebo. Improvements in peak FEV1(0-24h), trough FEV1 and pre-dose PEFam/pm with both dosing regimens versus placebo were statistically significant (all p < 0.01), with no statistically significant differences between the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. Lung function improvements with tiotropium Respimat(®) add-on to medium-dose ICS were sustained and similar for once-daily 5 μg and twice-daily 2.5 μg, supporting tiotropium Respimat(®) 5 μg as a once-daily bronchodilator that provides efficacy over the whole 24-h dosing interval in patients with symptomatic asthma. ClinicalTrials.gov identifier: NCT01152450.

Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials.

BackgroundTiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat® Soft Mist™ Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy.MethodsCombined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler® 18 μg and/or tiotropium Respimat® (1.25-, 2.5-, 5.0- and 10-μg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days.ResultsFour trials (n = 727) were included in the analysis. Respimat® (1.25–10 μg) or HandiHaler® (18 μg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure–effect relationship.ConclusionsIn this analysis, tiotropium maintenance therapy administered using Respimat® (1.25–10 μg) or HandiHaler® (18 μg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.

Tiotropium respimat® add-on therapy reduces airflow obstruction in patients with symptomatic moderate asthma, independent of TH2 inflammatory status

S A T U R D A Y 16 Tiotropium Respimat Add-On Therapy Reduces Airflow Obstruction In Patients With Symptomatic Moderate Asthma, Independent Of TH2 Inflammatory Status Dr. Thomas B. Casale, MD, FAAAAI, Dr. Eric Donn Bateman, MD, Prof. Ronald Dahl, MD, Dr. Emilio Pizzichini, Dr. Mark L. Vandewalker, MD, Dr. Johann Christian Virchow, Dr. Michael Engel, MD, Dr. Petra Moroni-Zentgraf, Dr. Hendrik Schmidt, Huib A. M. Kerstjens; Univeristy Of South Florida Morsani College Of Medicine, Tampa, FL, University of Cape Town Lung Institute, Cape Town, South Africa, Odense University Hospital, Odense, Denmark, NUPAIVA (Asthma Research Centre), Universidade Federal de Santa Catarina, Florian opolis, Brazil, Clinical Research of the Ozarks, Columbia, MO, University Clinic Rostock, Rostock, Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim Am Rhein, Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. RATIONALE: In patients with symptomatic asthma receiving ICS or ICS+LABA, Phase III studies have demonstrated improved lung function with tiotropium Respimat , a once-daily long-acting anticholinergic bronchodilator. The efficacy of some treatments (e.g. ICS and omalizumab) appears higher in TH2-high phenotypes, but no specific treatments are available that work equally well in both TH2-high and TH2-low phenotypes. We explored whether TH2 biomarker status influenced responses to tiotropium in patients with moderate symptomatic asthma. METHODS: In two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group trials (NCT01172808/NCT01172821), patients with moderate symptomatic asthma, using medium-dose ICS (400-800 mg budesonide equivalent), were administered once-daily tiotropium Respimat 5 mg or 2.5 mg, placebo, or salmeterol (active comparator without inferential analysis). Co-primary endpoints included peak and trough FEV1 response (difference from baseline) at 24 weeks. Pre-planned analyses (pooled population) were performed in TH2-low and TH2-high subgroups defined at baseline as total serum IgE 430 mg/L or blood eosinophils 0.6310/L. RESULTS: Of 1545 patients in the full analysis set who received tiotropium or placebo, 915/1455 were reported with IgE >430 mg/L and 300/1461 with an eosinophil count of >0.6310/L. Peak FEV1 improved with tiotropium versus placebo, independent of IgE (p<0.0001 both doses) and eosinophil count (p<0.0001 both doses). Trough FEV1 also improved with tiotropium versus placebo, independent of IgE (p<0.0001 both doses) and eosinophil count (p<0.005 both doses). CONCLUSIONS: Once-daily tiotropium Respimat as add-on to ICS reduces airflow obstruction in patients withmoderate symptomatic asthma, independent of TH2 phenotype, and thus may potentially provide an important therapeutic option.

P260 Tiotropium Respimat(R) Add-on To Inhaled Corticosteroids Improves Lung Function In Patients With Symptomatic Mild Asthma: Results From A Phase Iii Trial

Background Despite currently available therapies and detailed guidelines, many people with mild asthma remain symptomatic; it is important to establish the efficacy and safety of new treatments in this group. Methods A Phase III, randomised, double-blind, parallel-group trial (GraziaTinA-asthma ® ; NCT01316380) evaluated the efficacy and safety of once-daily tiotropium 5 µg or 2.5 µg versus placebo (all delivered via the Respimat ® SoftMist™ inhaler) for 12 weeks in patients with symptomatic asthma on low-dose inhaled corticosteroids (200–400 µg budesonide or equivalent). The primary end point was peak forced expiratory volume in 1 second (FEV 1 ) within 3 h of dosing (0–3h) response (change from baseline) at 12 weeks. Secondary end points were trough FEV 1 , FEV 1 area under the curve (AUC) (0–3h) and peak expiratory flow responses (measured with the AM2+ ® device), and seven-question Asthma Control Questionnaire (ACQ-7) score. Results Of 464 treated patients, 155 received tiotropium Respimat ® 5 µg, 154 received tiotropium Respimat ® 2.5 µg and 155 received placebo Respimat ® . Both tiotropium Respimat ® doses were superior to placebo Respimat ® in peak FEV 1(0–3h) response (adjusted mean difference: 5 µg, 128 mL; 2.5 µg, 159 mL; both p 1 response (adjusted mean difference: 5 µg, 122 mL, p = 0.001; 2.5 µg, 110 mL, p = 0.003). FEV 1 AUC (0–3h) response at each visit, versus placebo Respimat ® , significantly favoured tiotropium Respimat ® 5 µg (p = 0.009 to p ® , each week, all favoured tiotropium Respimat ® 5 µg (all p ® 5 µg, 1.391; tiotropium Respimat ® 2.5 µg, 1.438; placebo Respimat ® , 1.377). Adverse events were predominantly mild or moderate and were balanced between treatment groups. Conclusion Tiotropium Respimat ® was effective and well tolerated in patients with symptomatic mild asthma despite low-dose inhaled corticosteroid treatment.

P262 Tiotropium Safety And Performance In Respimat(R) (tiospir ): Safety And Efficacy In Patients With Tiotropium Handihaler(R) Use At Baseline

Introduction The TIOSPIR™ trial showed that tiotropium Respimat ® and HandiHaler ® have similar safety and exacerbation efficacy profiles in patients with chronic obstructive pulmonary disease (COPD). We present here results for patients from the United States (US) using tiotropium HandiHaler ® at baseline. Methods TIOSPIR™ (n = 17,135), a 2–3 year, randomised, double-blind, parallel-group, event-driven trial, compared safety and efficacy of once-daily tiotropium Respimat ® 5 and 2.5 µg with once-daily HandiHaler ® 18 µg in patients with COPD. Primary endpoints were time to death and time to first COPD exacerbation. Safety, including cardiovascular safety, was assessed. Tiotropium Respimat ® was unavailable in the US (baseline tiotropium HandiHaler ® use only), therefore this subgroup was analysed. Results Overall, 1779 patients from TIOSPIR™ treated with tiotropium HandiHaler ® 18 µg at baseline in the US were randomised and treated (n = 572, n = 602 and n = 605 for tiotropium Respimat ® 2.5 and 5 µg and HandiHaler ® 18 µg). A numerically lower time to death was observed for patients within the Respimat ® groups versus HandiHaler ® (vital status follow up: Respimat ® 5 µg: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.53–1.12; Respimat ® 2.5 µg: HR, 0.76; 95% CI, 0.52–1.12). Risk of major adverse cardiovascular event (MACE) and fatal MACE was numerically lower for the Respimat ® groups versus HandiHaler ® (MACE: Respimat ® 5 µg: HR, 0.69; 95% CI, 0.41–1.18; Respimat ® 2.5 µg: HR, 0.83; 95% CI, 0.50–1.39; fatal MACE: HR, 0.60; 95% CI, 0.26–1.37; Respimat ® 2.5 µg: HR, 0.42; 95% CI, 0.16–1.09). Overall incidence of a fatal event (on-treatment) was lower in the Respimat ® groups versus HandiHaler ® (Respimat ® 5 µg: HR, 0.60; 95% CI, 0.39–0.92; Respimat ® 2.5 µg: HR, 0.67; 95% CI, 0.44–1.02). Time to first exacerbation was similar across groups (Respimat ® 5 µg versus HandiHaler ® : HR, 0.94; 95% CI, 0.82–1.08). Conclusions Patients treated with tiotropium HandiHaler ® 18 µg at baseline, and who were randomised and subsequently received tiotropium Respimat ® 2.5 or 5 µg, had a similar risk of exacerbation as patients who continued to be treated with tiotropium HandiHaler ® 18 µg. In this subgroup of patients, all-cause mortality was similar between tiotropium Respimat ® and HandiHaler ® 18 µg. Abstracts M263 to M272 are found on page A218–A223.

S92 Efficacy Of Once-daily Tiotropium Respimat(R) 5 g From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Recent clinical trials have indicated that the long-acting antimuscarinic agent tiotropium, a once-daily long-acting bronchodilator, may provide benefit to patients with symptomatic asthma. We investigated primary efficacy data (lung function, risk of severe exacerbation and seven-question Asthma Control Questionnaire [ACQ-7] response) from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium add-on versus placebo add-on (all tiotropium doses delivered via the Respimat ® SoftMist™ inhaler) in adults with symptomatic asthma on inhaled corticosteroid (ICS) ± long-acting β 2 -agonist (LABA) maintenance therapy. Methods Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). Results 3476 patients were treated, of whom 1128 received tiotropium Respimat ® 5 µg. Once-daily tiotropium Respimat ® 5 µg significantly improved lung function (Table) in patients with not fully controlled asthma receiving low- to high-dose ICS. In addition, tiotropium Respimat ® 5 µg reduced the risk of severe exacerbations versus placebo (co-primary end point) in patients on high-dose ICS + LABA (hazard ratio 0.79; p = 0.0343), and there was an increase in ACQ-7 responder rate (co-primary end point) with the5 µg dose (odds ratio 1.32; p = 0.0308) compared with placebo in patients on moderate-dose ICS. Conclusion Once-daily tiotropium Respimat ® significantly improves lung function in adult patients with symptomatic asthma receiving a range of doses of ICS, including even high-dose ICS + LABA, suggesting a potential role for this treatment as add-on to ICS in adults with symptomatic asthma.

P229 Once-daily Tiotropium Respimat(R) As Add-on To At Least Medium- To High-dose Ics, With Or Without Laba, Improves Lung Function In Patients With Symptomatic Asthma, Independent Of Allergic Status

Background A substantial number of patients have symptomatic asthma despite treatment according to guidelines. Several studies have confirmed that tiotropium Respimat ® , a once-daily long-acting anticholinergic bronchodilator, improves lung function in symptomatic patients receiving at least medium-dose inhaled corticosteroids (ICS) + long-acting β 2 -agonist (LABA) (Kerstjens et al . NEJM 2012;367:1198–207; Bateman et al . JACI 2011;128:315–22). Here we examine whether the atopic and/or allergic status of patients in these trials influenced their response to tiotropium Respimat ® . Method Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients (n = 912) on high-dose ICS + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients (n = 2100) on moderate-dose ICS. Pre-planned analyses (pooled populations) were performed in two subgroups defined at baseline as total serum immunoglobulin E (IgE) ≤ or >430 μg/L or blood eosinophils ≤ or >0.6×10 9 /L or clinical judgement of allergic status (‘No’ or ‘Yes’). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results Tiotropium Respimat ® 5 µg or 2.5 µg improved peak and trough forced expiratory volume in 1 second versus placebo (Table) independent of IgE, eosinophil count and clinical judgement. Conclusion Once-daily tiotropium Respimat ® as add-on to ICS or ICS + LABA in patients with moderate to severe symptomatic asthma reduces airflow obstruction, apparently independent of their atopic and/or allergic status.

P231 Once-daily Tiotropium Respimat(R): Safety And Tolerability Results From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Tiotropium Respimat ® , a once-daily long-acting anticholinergic agent, is effective as add-on to inhaled corticosteroids (ICS) ± a long-acting β2-agonist (LABA) in adults with symptomatic asthma. Safety and tolerability are key issues in the development of new therapies or established therapies in new disease areas. We present key safety data from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium Respimat ® versus placebo in adults with symptomatic asthma. Methods: Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results: 3476 patients were treated. Incidence of any adverse events (AEs), serious AEs and investigator-defined drug-related AEs was similar across treatment groups within each trial. AEs reported by ≥5% of patients were similar across all treatment groups within each trial (Table). The number of cardiovascular AEs was small in all five studies and comparable between tiotropium Respimat ® and placebo. No deaths occurred in any trial. Conclusion: Once-daily tiotropium Respimat® is well tolerated and comparable with placebo in adult patients with symptomatic asthma receiving at least low- to high-dose ICS.

S91 Once-daily tiotropium Respimat(R) add-on to ICS + LABA improves symptom control and reduces exacerbations in patients with symptomatic asthma

Background We evaluated the effect of once-daily tiotropium Respimat® 5 µg on lung function, asthma exacerbation and asthma symptom control among patients with symptomatic asthma receiving inhaled corticosteroids (ICS; ≥800 μg/day budesonide or equivalent) + long-acting β2-agonist (LABA). Methods Data were pooled from two replicate, double-blind, placebo-controlled, 48-week, parallel-group studies of once-daily tiotropium 5 µg versus placebo, both delivered via the Respimat® SoftMist™ inhaler (PrimoTinA-asthma®: [NCT00772538][1], [NCT00776984][2]). Eligible patients had: ≥5-year history of asthma diagnosed before the age of 40 years; seven-question Asthma Control Questionnaire (ACQ-7) score of ≥1.5; experienced ≥1 exacerbation during the previous year. Patients were either lifelong non-smokers, or ex-smokers (<10 pack-years) who quit smoking ≥1 year before study enrolment. Exclusion criteria included diagnosis of chronic obstructive pulmonary disease. Co-primary end points in individual trials: peak forced expiratory volume in 1 second (FEV1) within 3 h post-dose (0–3 h) and trough FEV1. A co-primary end point in pooled data was time to first severe exacerbation; secondary end points included time to first episode of asthma worsening and ACQ-7 response. Post hoc efficacy analyses were performed. Results 912 patients were randomised to receive tiotropium Respimat® (n = 456) or placebo Respimat® (n = 456). At Week 48, tiotropium Respimat® was associated with statistically significant improvements versus placebo Respimat® in peak FEV1(0–3h) (adjusted mean difference 100 mL; 95% confidence interval: 52, 148; p < 0.0001) and trough FEV1 (adjusted mean difference 62 mL; 95% confidence interval: 18, 106; p = 0.006). Time to first severe asthma exacerbation was significantly longer with tiotropium Respimat® versus placebo Respimat® (282 vs 226 days, respectively; hazard ratio 0.79; p = 0.034), as was time to first episode of asthma worsening (315 vs 181 days, respectively; hazard ratio 0.69; p < 0.0001). At Week 24, ACQ-7 responder rate was significantly higher with tiotropium Respimat® (53.9%) versus placebo Respimat® (46.9%; odds ratio 1.32; p = 0.0427). Conclusion Once-daily tiotropium Respimat® add-on to ICS + LABA improves lung function, reduces risk of severe asthma exacerbation and asthma worsening, and significantly improves asthma symptom control compared with placebo Respimat® in patients with symptomatic asthma. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00772538&atom=%2Fthoraxjnl%2F69%2FSuppl_2%2FA49.3.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00776984&atom=%2Fthoraxjnl%2F69%2FSuppl_2%2FA49.3.atom

P261 Tiotropium Safety And Performance In Respimat(R) (tiospir ): Safety And Efficacy In Patients Naive To Treatment With Anticholinergics

Introduction The TIOSPIR™ trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat ® and HandiHaler ® in patients with chronic obstructive pulmonary disease (COPD). We present here the results for patients who were naive to anticholinergic treatment at baseline. Methods TIOSPIR™ (n = 17,135), a 2–3 year, randomised, double-blind, parallel-group, event-driven trial, compared safety and efficacy of once-daily tiotropium Respimat ® 5 and 2.5 µg with HandiHaler ® 18 µg in patients with COPD. Primary endpoints were time to death (noninferiority of Respimat ® 5 or 2.5 μg versus HandiHaler ® ) and time to first COPD exacerbation (superiority of Respimat ® 5 μg versus HandiHaler ® ). Safety, including cardiovascular safety, was assessed. Results Overall, 6966 patients from TIOSPIR™, naive to anticholinergic treatment at baseline, were randomised and treated (n = 2345, n = 2312 and n = 2309 for tiotropium Respimat ® 2.5 and 5 µg and HandiHaler ® 18 µg). There was similar risk of death (vital status follow up) (measured as time to death) for the Respimat ® groups versus HandiHaler ® (Respimat ® 5 µg: hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.75–1.17; Respimat ® 2.5 µg: HR, 1.05; 95% CI, 0.84–1.30) with similar results for the on-treatment sensitivity analysis (Respimat ® 5 µg: HR, 0.91; 95% CI, 0.71–1.17; Respimat ® 2.5 µg: HR, 1.11; 95% CI, 0.87–1.40). Risk of exacerbation was also similar for the Respimat ® groups versus HandiHaler ® (measured as time to first exacerbation) (Respimat ® 5 µg: HR, 0.99; 95% CI, 0.90–1.08; Respimat ® 2.5 µg: HR, 1.04; 95% CI, 0.95–1.14). Risk of major adverse cardiovascular event (MACE) or fatal MACE were similar for the Respimat ® groups versus HandiHaler ® (MACE: Respimat ® 5 µg: HR, 1.20; 95% CI, 0.88–1.63; Respimat ® 2.5 µg: HR, 1.11; 95% CI, 0.81–1.51; fatal MACE: Respimat ® 5 µg: HR, 1.14; 95% CI, 0.75–1.71, Respimat ® 2.5 µg: HR, 1.12; 95% CI, 0.75–1.69). Conclusions Analogous to the global analysis, patients naive to anticholinergic treatment and treated with tiotropium Respimat ® 2.5 or 5 µg or HandiHaler ® in the TIOSPIR™ trial exhibited similar safety and exacerbation efficacy profiles.

P259 Tiotropium Handihaler(R) And Respimat(R) In Copd: A Safety Analysis On Pooled Data

Rationale Tiotropium has been approved and marketed via HandiHaler® (18 µg once daily [qd]) since 2002 and via Respimat® (5 µg qd) since 2007. The recent TIOSPIR™ (TIOtropium Safety and Performance In Respimat®) study demonstrated that both products had comparable safety profiles; the objective of this analysis was to provide an updated safety evaluation of tiotropium in both formulations. Methods Analysis of pooled adverse events (AEs) from randomised, double-blind, parallel-group, placebo-controlled clinical trials of ≥4 weeks’ duration where either tiotropium HandiHaler® 18 µg or tiotropium Respimat® 5 µg was indicated for chronic obstructive pulmonary disease (COPD). Rate ratios (RRs), incidence rates (IRs) and 95% confidence intervals (CIs) were determined for HandiHaler® and Respimat® trials together and separately. Results This analysis of 28 HandiHaler® and seven Respimat® studies provided 14,909 (12,469 and 2440 with HandiHaler® and Respimat®, respectively) patient-years’ exposure to tiotropium. Mean age was 65 years and mean forced expiratory volume in 1 second was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and serious AEs (0.94 [0.89, 0.99]) was significantly lower with a numerically lower risk of death (0.90 [0.79, 1.01]) in the tiotropium group (pooled results) (Table). When separated by device, the risk of AEs and serious AEs remained lower in the tiotropium groups than placebo: RR 0.88 and 0.94 for HandiHaler® and 0.94 and 0.94 for Respimat® for AEs and serious AEs, respectively. Risks for cardiac events (0.93 [0.85, 1.02]) and major adverse cardiovascular events (MACE) (0.87 [0.75, 1.01]) were numerically lower and risk for respiratory, thoracic and mediastinal disorders (0.76 [0.61, 0.96]) was significantly reduced in the tiotropium group. The typical anticholinergic effects of dry mouth (2.39 [2.01, 2.84]), constipation (1.28 [1.06, 1.54]), intestinal obstruction (3.80 [1.42, 10.12]), dysuria (2.16 [1.31, 3.57]) and urinary retention (1.93 [1.21, 3.09]) were higher in the tiotropium group. Conclusions The results from this safety review do not indicate an increased overall risk for fatal or cardiovascular events during tiotropium treatment, given via HandiHaler® or Respimat®, in patients with COPD.