A placebo-controlled, crossover trial to investigate the efficacy of tiotropium bromide or placebo added to usual care in stable symptomatic post-hematopoietic stem cell transplantation (HSCT) bronchiolitis obliterans syndrome (BOS).

BACKGROUND: Despite the fundamental progress in hematopoietic stem cell transplant, this treatment is also associated with complications. Graft-versus-host disease is a possible complication of HSCT. Bronchiolitis obliterans syndrome (BOS) is the pulmonary form of this syndrome. Due to the high morbidity and mortality rate of BOS, various studies have been conducted in the field of drug therapy for this syndrome, although no standard treatment has yet been proposed. According to the hypotheses about the similarities between BOS and chronic obstructive pulmonary disease, the idea of using tiotropium bromide as a bronchodilator has been proposed. METHOD/DESIGN: A randomized, double-blind, placebo-controlled, and crossover clinical trial is being conducted to evaluate the efficacy of tiotropium in patients with BOS. A total of 20 patients with BOS were randomly assigned (1:1) to receive a once-daily inhaled capsule of either tiotropium bromide (KP-Tiova Rotacaps 18 mcg, Cipla, India) or placebo for 1 month. Patients will receive tiotropium bromide or placebo Revolizer added to usual standard care. Measurements will include spirometry and a 6-min walking test. ETHICS/DISSEMINATION: This study was approved by the Research Ethics Committees of Imam Khomeini Hospital Complex, Tehran University of Medical Science. Recruitment started in September 2022, with 20 patients randomized. The treatment follow-up of participants with tiotropium is currently ongoing and is due to finish in April 2024. The authors will disseminate the findings in peer-reviewed publications, conferences, and seminar presentations. TRIAL REGISTRATION: Iranian Registry of Clinical Trial (IRCT) IRCT20200415047080N3. Registered on 2022-07-12, 1401/04/21.

EFFICACY OF COMBINATION OF TIOTROPIUM/OLODATEROL IN PATIENTS WITH COPD IN REAL CLINICAL PRACTICE.

OBJECTIVE: The aim: Show the efficacy of the Tiotropium / olodaterol combination in real clinical practice. PATIENTS AND METHODS: Materials and methods: 100 patients with the diagnosis of COPD were included onto the study during the period of 2019-2020, an average age was 64.09±1.94 years, 66 were men (66 %) and 34 were women (34 %). There were 68 % of smokers with the average smoking experience of 24.44±4.84 pack-years. Average COPD duration was 9.35±2.42 years. There were 3 visits in the study - visit 1 (baseline), visit 2 (4-6 weeks) visit 3 (1 year). Source documentation was assessed at visit 1 and visit 3 for amount of exacerbations, antibiotic, glucocorticosteroid, methylxanthines use; mMRC and CAT were assessed at all visits. RESULTS: Results: Combined therapy with tiotropium/olodaterol improves clinical course of COPD, which is characterized by the significant decreased of the amount of exacerbations (2.63±0.29 to 1.63±0.21) and hospital admissions (1.2±0.2 tо 0.37±0.11). Improvement of symptoms and amount of exacerbation leads to much less use of antibiotics and glucocorticosteroids. A part of patients that used antibiotics decreased from 86±6.9 % to 67±9.3 %, amount of antibiotic courses from 1.37±0.17 tо 0.88±0.15, duration of treatment with antibiotics from 10.85±1.53 to 6.12±1.17 days. Part of the patients that used glucocorticosteroids decreased from 50±9.9 % tо 30±9.1 %, duration of treatment with antibiotics reduced from 3.97±1.06 tо 1.86±0.91 days. There also was a tendency towards a lesser used of methylxanthines. Combined therapy with tiotropium/olodaterol significantly decreased symptoms of COPD according to the mMRC (2.3±0.14 to 1.87±0.15) and САТ (23.28±1.71 to 15.77±1.58). CONCLUSION: Conclusions: Tiotropium/olodaterol combination showed its efficacy in real clinical practice. There was significant reduction in amount of exacerbation and antibiotic, gluco¬corticosteroid use during the study, which was also accompanied by the reduction is symptoms.

Randomized controlled trial of triple versus dual inhaler therapy on small airways in smoking asthmatics.

BACKGROUND: Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control. OBJECTIVES: We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers. METHODS: Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP). RESULTS: After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different. CONCLUSIONS: ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke.

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

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

The pharmacokinetics, pharmacodynamics and tolerability of PUR0200, a novel tiotropium formulation, in chronic obstructive pulmonary disease.

AIMS: PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV1 ) trough and (0-24 h) and pharmacokinetic parameters. RESULTS: The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV1 , with 3 µg demonstrating a lower effect than higher doses. The placebo-adjusted mean (95% confidence interval) increases from baseline at 24 h postdose were 150 ml (100-200), 210 ml (160-270) and 200 ml (140-250) for 3 µg, 6 µg and 9 µg doses of PUR0200, respectively. Tiotropium HH (18 µg) caused a mean 169 ml (standard deviation 157ml) improvement in trough FEV1 , which was not significantly different to the PUR0200 effects at any of the tested doses. CONCLUSIONS: PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH.

Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial.

BACKGROUND: Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. METHODS: This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 µg-5 µg or tiotropium 5 µg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. FINDINGS: Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium-olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium-olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85-1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments. INTERPRETATION: Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. FUNDING: Boehringer Ingelheim International GmbH.

Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR® trial.

Background: Although 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 methods: TIOSPIR 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. Results: TIOSPIR 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. Conclusion: Although 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 number: NCT01126437.

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

INTRODUCTION: Geographical 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. METHODS: TIOSPIR®, 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. RESULTS: At 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). CONCLUSIONS: TIOSPIR® 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.

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

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

Bronchodilator efficacy of 18 µg once-daily tiotropium inhalation via Discair® versus HandiHaler® in adults with chronic obstructive pulmonary disease: randomized, active-controlled, parallel-group, open-label, Phase IV trial.

PURPOSE: To compare the bronchodilator efficacy of 18 µg once-daily tiotropium inhalation administered via Discair® versus HandiHaler® in adults with moderate-to-severe chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: Fifty-eight patients with moderate-to-severe COPD were enrolled in this randomized, active-controlled, parallel-group, open-label, Phase IV non-inferiority trial. Patients were randomly assigned to a test group (n=29, inhalation with Discair) or a reference group (n=29, inhalation with HandiHaler). The primary efficacy parameter was the average maximum change in forced expiratory volume in 1 second (FEV1, in L). Change in forced vital capacity (FVC, in L), %FEV1 and %FVC, the standardized area under the response-time curve (AUC) for the absolute change in FEV1 and FVC, time to onset and peak of response, and safety data were also evaluated. RESULTS: The test inhaler was non-inferior to the reference inhaler in terms of maximum change in FEV1 at 24 h (unadjusted change: 0.0017 L [95% confidence interval [CI]: -0.0777, 0.0812]; change adjusted for time to reach maximum change in FEV1 and smoking in pack-years: 0.0116 L [95% CI: -0.0699, 0.0931]), based on a non-inferiority margin of 0.100 L. There were also no significant differences between the two groups in maximum change in FVC value from baseline (0.3417 L vs 0.4438 L, P=0.113), percent change from baseline (22.235 vs 20.783 for FEV1, P=0.662; 16.719 vs 20.337 for FVC, P=0.257), and AUC0-24 h (2.949 vs 2.833 L for FEV1, P=0.891; 2.897 vs 4.729 L for FVC, P=0.178). There were no adverse events, serious adverse events, or deaths. CONCLUSION: Our findings show that the Discair was non-inferior to the HandiHaler. More specifically, these devices had similar clinical efficacy in terms of time-dependent response over 24 h for patients with moderate-to-severe COPD.

The efficacy and safety of combined tiotropium and olodaterol via the Respimat(®) inhaler in patients with COPD: results from the Japanese sub-population of the Tonado(®) studies.

BACKGROUND: The efficacy and safety of once-daily tiotropium + olodaterol (T+O) maintenance treatment was demonstrated in the large, multinational, replicate, randomized, Phase III, Tonado(®) 1 (NCT01431274) and 2 (NCT01431287) studies in patients with moderate to very severe COPD. However, there may be racial differences in the effects of T+O on lung function in patients with COPD. METHODS: In this Tonado(®) subgroup analysis, we assessed efficacy and safety of T+O in Japanese participants. RESULTS: Versus the overall population, the 413 Japanese patients randomized and treated were slightly older, with more men, lower body mass index, lower baseline St George's Respiratory Questionnaire (SGRQ) scores, fewer current smokers, but with higher pack-year smoking history. A lower proportion of Japanese patients used inhaled corticosteroids, short-acting muscarinic antagonists, or short- or long-acting ß-adrenergic agonists at baseline, but use of long-acting muscarinic antagonists was higher. At Week 24, mean improvements with T+O 5/5 µg in forced expiratory volume in 1 second area under the curve from 0-3 hours response were 151 mL versus olodaterol and 134 mL versus tiotropium 5 µg; mean improvements with T+O 2.5/5 µg were 87 mL versus olodaterol and 70 mL versus tiotropium 2.5 µg. Mean improvements with T+O 5/5 µg in trough forced expiratory volume in 1 second were 131 mL versus olodaterol and 108 mL versus tiotropium 5 µg; mean improvements with T+O 2.5/5 µg were 60 mL versus olodaterol and 47 mL versus tiotropium 2.5 µg. SGRQ scores improved from baseline to a greater extent with both doses of T+O versus monotherapies. Responses were similar in the overall population. Adverse-event incidence was generally balanced across treatment groups. CONCLUSION: Consistent with results from the overall population, T+O 5/5 µg was superior to each monotherapy for lung function and SGRQ in the Japanese sub-population of patients with COPD in Tonado(®).

Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial.

BACKGROUND: Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid (ICS) maintenance therapy. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma. METHODS: In this 48-week, double-blind, placebo-controlled, parallel-group study, 398 patients aged 12 to 17 years were randomized to receive 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to ICS background therapy, with or without a leukotriene receptor antagonist; long-acting ß2-agonist therapy was not permitted during the study. RESULTS: Improvement in peak FEV1 within 3 hours after dosing at 24 weeks (primary end point) was statistically significant with both tiotropium doses compared with placebo: 5 µg of tiotropium, 174 mL (95% CI, 76-272 mL); 2.5 µg of tiotropium, 134 mL (95% CI, 34-234 mL). Significant improvements in trough FEV1 at week 24 (a secondary end point) were observed with the 5-µg dose only. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed. CONCLUSIONS: Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma. Larger responses were observed with the 5-µg tiotropium dose.

Efficacy and Safety of Aclidinium/Formoterol versus Tiotropium in COPD: Results of an Indirect Treatment Comparison.

INTRODUCTION: The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 µg twice daily compared to tiotropium 18 µg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George's Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control. RESULTS: Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI -2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB -0.52 (95% CrI -2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization. CONCLUSION: Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile. FUNDING: AstraZeneca.

Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis.

BACKGROUND: The role of tiotropium for the treatment of adolescents with asthma has not yet been clearly defined. OBJECTIVE: To assess the efficacy and safety of inhaled tiotropium in adolescents with moderate to severe symptomatic asthma. METHODS: Randomized, placebo-controlled trials were included in this systematic review. Primary outcomes were peak and trough forced expiratory volume in 1 second (FEV1). RESULTS: Three studies (approximately 1,000 patients) were included. Tiotropium was associated with significant improvements in FEV1 peak (mean change from baseline) by 120 mL (P < .001) and trough by 100 mL (P < .001) compared with placebo. Tiotropium significantly reduced the percentage of patients who experienced an Asthma Control Questionnaire 7 worsening episode defined as a change from trial baseline of 0.5 points or more compared with placebo (2.1% vs 4.8%, number needed to treat = 38) and also was associated with a significantly decreased in the number of patients with at least one exacerbation compared with placebo (17.6 vs 23.8%, number needed to treat = 16). Finally, no significant differences were found in rescue medication use, withdrawals, withdrawals due to adverse events (AEs), AEs (27.3% vs 27.1%), and serious AEs (6.5% vs 7.1%). Tiotropium in doses of 2.5 µg once daily or 5.0 µg once daily resulted in equivalent effects. CONCLUSIONS: Tiotropium was well tolerated and efficacious as an addition to maintenance treatment with an inhaled corticosteroid or an inhaled corticosteroid plus a long-acting ß-agonist in adolescents with moderate to severe asthma. Available data do not suggest an advantage of the 5-µg once-daily dose (used in adults) compared with the 2.5-µg once-daily dose of tiotropium.

Safety, tolerability, and plasma exposure of tiotropium Respimat® in children and adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (CF) suffer from chronic lung disease that is often treated with a bronchodilator. This trial evaluated the pharmacokinetics, safety, and tolerability of single and multiple doses of tiotropium inhaled via the Respimat® Soft Mist™ Inhaler in patients with CF. METHODS: Patients received a single dose (placebo, 2.5 µg, 5 µg, or 10 µg) and/or multiple doses (placebo, 2.5 µg, or 5 µg) of tiotropium daily for 28 days. RESULTS: Ninety-two patients, aged 5-57 years, were treated. All doses showed a satisfactory safety profile for adverse events, vital signs, laboratory evaluations, and physical examination. At steady-state, peak exposure to tiotropium was comparable between adult patients with CF and patients with chronic obstructive pulmonary disease. CONCLUSIONS: Tiotropium 2.5 µg or 5 µg inhaled via the Respimat® Soft Mist™ Inhaler once daily was well tolerated in patients with CF.

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

BACKGROUND: Tiotropium 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. METHODS: Combined 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. RESULTS: Four 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. CONCLUSIONS: In 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.