Astım tedavisinde Tiotropium’un yeri Dr. Haluk Türktaş Gazi Üniversitesi Ankara

Çıkar Çatışması Kongre desteği, konuşma veya danışmanlık ücreti AstraZeneca Boehringer Ingelheim GlaxoSmithKline MSD

İnhaler steroid veya İKS+LABA ile kontrol altına alınamayan orta-ağır astımlı hastalarda İnhaler steroid+Tiotropium İnhaler steroid+LABA+Tiotropium

KOAH tanısı olmayan Uzun zamandır astımı olan Sigara öyküsü olmayan Reversible obstrüksiyonu olan

SFT FP 500+SALM+Plasebo n:18 FP 500+SALM+Tiotropium 4 hafta Stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma Tom Fardon Respir Med 2007: 101; 1218–1228 n:18 Ağır astım İCS FP 1000 μg SFT 4 hafta FP 500+SALM+Plasebo Crossover FP 500+SALM+Tiotropium LAMA as add on to ICS/LABA Summary We conducted a double blind, randomised, placebo-controlled, crossover study evaluating the effects of halving inhaled steroid dosage plus salmeterol, or salmeterol and tiotropium. Eighteen life-long non-smoking severe asthmatics [mean FEV1 1.49 l (51%)] were run-in for 4 weeks on HFA-fluticasone propionate 1000 mg daily, and were subsequently randomised to 4 weeks of either (a) HFA-fluticasone propionate 500 mg BD/ salmeterol 100 mg BD/HFA-tiotropium bromide18 mg od; or (b) fluticasone propionate 500 mg BD/salmeterol 100 mg BD matched placebo. Measurements of spirometry and body plethysmography were made. Adding salmeterol to half the dose of fluticasone led to a mean improvement (95% CI) vs. baseline in morning PEF of 41.5 (14.0–69.0) l/min [po0.05]; and RAWof 0.98 (0.14–1.8) cm H2O/l/s [po0.05]. Adding salmeterol/tiotropium produced similar improvements in PEF and RAW, but also improved FEV1 by 0.17 (0.01–0.32) l [po0.05]; FVC 0.24 (0.05–0.43) l [po0.05] and reduced exhaled NO by 2.86 (0.12–5.6) ppb [po0.05]. RV and TLC were not altered by either treatment; there were no significant changes in symptoms or quality of life compared with baseline. Addition of salmeterol/tiotropium to half the dose of fluticasone afforded small, but significant improvements in pulmonary function. These effects were not associated with commensurate changes in subjective symptoms or quality of life.

Stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma Tom Fardon Respir Med 2007: 101; 1218–1228 Sonuçlar: Salmeterol eklenmesi ile sağlanan düzelmeler Sabah PEF 41 L/dk FEV1 0.11 L RAW -%33 Salmeterol +Tiotropium eklenmesi ile sağlanan düzelmeler Sabah PEF 55L/dk FEV1 0.17 L RAW -%34 FeNO -2.86 ppb Düzelme sağlanamayanlar TLC veya RV Semptom, yaşam kalitesi Figure 2 Pulmonary function results as FEV1% predicted for all treatments. FP 1000—fluticasone 1000 mg daily; FP 500/SM/ PL—fluticasone 500 mg daily, salmeterol 50 mg BD and placebo BD; FP 500/SM/TIO—fluticasone 500 mg daily, salmeterol 50 mg BD and tiotropium 18 mg OD. *Denotes a difference of po0.05

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma Stephen P. Peters. Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) study NHLBI Asthma Clinical Research Network N Engl J Med 2010;363:1715-26 n:210 Hafif-orta astım İCS BDP 160 μg ICS+Tiotropium (18 μg) FEV1 PEF Astım kontrol 14 hafta ICS+Salmeterol (2x50μg) İki kat doz BDP (320 μg) Crossover LAMAor LABA as add on to ICS Hafif-orta kontrol altına olmayan astımlı hastalarda iki kat doz steroid için superiorite, salmeterol için non-inferiority çalışması Methods In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). Results The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthmacontrol days, with a difference of 0.079 (P = 0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P = 0.004); and daily symptom scores, with a difference of −0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P = 0.003). Conclusions When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma NHLBI Asthma Clinical Research Network N Engl J Med 2010;363:1715-26 We report two findings with implications for the treatment of asthma in adults. First, our study shows that the use of tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid for patients whose symptoms were inadequately controlled while they were receiving inhaled beclomethasone alone at a dose of 80 μg twice a day. Second, among patients in our study who were similar to those in trials showing the clinical efficacy of LABA therapy,3,4 tiotropium was noninferior to salmeterol on the basis of predefined criteria, a finding that meets the standards established in the FDA’s draft guidance for industry on noninferiority clinical trials.22

Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma Eric D. Bateman J Allergy Clin Immunol 2011;128:315-22 n:388 İCS (400-1.000 μg) Kontrolsüz astım Arg/Arg 16 PEF

Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma Eric D. Bateman J Allergy Clin Immunol 2011;128:315-22

FEV1 Tiotropium (5μg) n:107 Tiotropium (10μg) Plasebo 8 hafta Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial H.A.M.Kerstjens J Allergy Clin Immunol 2011;128:308-14 n:107 Yüksek doz İCS+LABA Kontrolsüz ağır astım Tiotropium (5μg) FEV1 8 hafta Tiotropium (10μg) Plasebo Crossover LAMA as add on to ICS/LABA Background: Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients. Objective: We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 mg daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, >1.5; postbronchodilator FEV1, <80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting b2-agonist. Methods: This was a randomized, double-blind, crossover study with three 8–week treatment periods. The primary end point was peak FEV1 at the end of each treatment period. Results: Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV1, 65% of predicted value), 100 completed all periods. Peak FEV1 was significantly higher with 5 mg (difference, 139 mL; 95% CI, 96- 181 mL) and 10 mg (difference, 170 mL; 95% CI, 128–213 mL) of tiotropium than with placebo (both P < .0001). There was no significant difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 mg: 86 mL [95% CI, 41-132 mL]; 10 mg: 113 mL [95% CI, 67-159 mL]; both P < .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 mg of tiotropium. Conclusion: The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting b2-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma.

Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial H.A.M.Kerstjens J Allergy Clin Immunol 2011;128:308-14 FIG 2. FEV1 (A) and FVC (B) responses relative to baseline values within 3 hours after dosing after 8 weeks of treatment. The difference in level at 0:00 h is the trough effect of tiotropium administered 24 hours earlier. The measurement obtained at baseline (visit 2 before any maintenance or study medication) is defined as the baseline value. At the on-treatment visits, this was immediately followed by the usual medication (including ICS plus LABA), and this in turn was followed by the study medication. Error bars represent SEMs. Arrows indicate the timing of the maintenance medication: ICS plus LABA. Tiotropium R5, 5 mg of tiotropium; Tiotropium R10, 10 mg of tiotropium. FIG 3. Twenty-four-hour FEV1 (A) and FVC (B) responses as shown in Fig 2 in the subgroup of patients with 24-hour assessments (n 5 67). The baseline value was defined on visit 2 before any maintenance or study medication. At the on-treatment visits, this was immediately followed by the usual medication (including ICS plus LABA), which was followed in turn by the study medication. The afternoon dosing of ICS plus LABA treatment was also taken. Error bars represent SEMs. Arrows indicate the timing of the maintenance medication: ICS plus LABA. Tio R5, 5 mg of tiotropium; Tio R10, 10 mg of tiotropium.

İCS+LABA+Tiotropium (5μg) Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207 n:912 İCS+LABA Kontrolsüz astım İCS+LABA+Plasebo İCS+LABA+Tiotropium (5μg) SFT Atak 48 hafta LAMA as add on to ICS/LABA Background Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting betaagonists (LABAs). Methods In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV1) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. Results The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P = 0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. Conclusions In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation.

İlk ağır atak için geçen süre: Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207 Risk reduction %21 (p=0.03) 86 ml 154 ml All on top of ICS+LABA İlk ağır atak için geçen süre: 282 vs 226 gün Background Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting betaagonists (LABAs). Methods In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV1) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. Results The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P = 0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. Conclusions In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation.

SONUÇ: İnhaler steroid veya İKS+LABA ile kontrol altına alınamayan orta-ağır astımlı hastalarda Tiotropium eklenmesi Solunum fonksiyonlarında ek artışlar Astım atağında azalma sağlıyor

Tiotropium’a daha iyi yanıt veren astımlı hasta alt grubu var mı?

Predictors of response to tiotropium versus salmeterol in asthmatic adults National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network J Allergy Clin Immunol 2013:132;1068-1074 Tiotropiuma daha iyi yanıt veren hasta alt grupları Kolinerjik tonusu yüksek hastalar (İstirahat kalp hızı düşük olanlar) Genç hastalar Salbutamol veya ipratropium ile reversibilitesi olanlar Tiotropium yanıtını etkilemeyen faktörler Cinsiyet Atopi IgE düzeyi Balgam eozinofilisi FeNO Astım süresi BMI Definitive recommendations concerning how to translate these findings into clinical practice cannot be made on the basis of these observations alone. Clearly, the findings need to be replicated in an independent study. However, if the findings were replicated, we could suggest that if a patient with asthma still has suboptimal asthma control after a trial of ICSs alone (ie, has asthma symptoms or rescue b-agonist use most days of the week and/or >2 awakenings per week for asthma and/or compromised lung function [FEV1 <70% of predicted value]), he or she should undergo spirometry before and after administration of 4 puffs of albuterol. Patients with airway obstruction, as demonstrated by a reduced FEV1/FVC ratio, a positive response to albuterol, or both, should be good candidates for treatment with tiotropium as an add-on therapy. Whether this strategy should be reserved for patients in whom combination ICS-LABA therapy ‘‘fails’’ or whether physicians and patients should have the option of adding either tiotropium or a LABA to an ICS when monotherapy does not produce adequate asthma control awaits further investigation. Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. Methods: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network’s Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs). Results: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n 5 90 and 78, respectively) and ACDs (n 5 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n 5 104) than salmeterol (n 5 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P 5 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. Conclusion: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.

Altgrup Analizleri Tiotropiuma daha iyi yanıt veren hasta alt grupları Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207 Altgrup Analizleri Tiotropiuma daha iyi yanıt veren hasta alt grupları Düşük % FEV1 i olanlar Erkekler Sigara içenler (10 pk/yıl dan az) Tiotropium yanıtını etkilemeyenler Reversibilite düzeyi Astım süresi BMI Allerjik olup olmadığı ACQ-7 Sistemik steroid kullanımı Subgroup Analyses The improvements in peak FEV1 in the tiotropium group, as compared with the placebo group (measured as the interaction between the subgroup and study treatment), tended to be higher in patients with a lower FEV1 as a percentage of the predicted value (trial 1, P = 0.03; trial 2, P = 0.56), in men (trial 1, P = 0.09; trial 2, P = 0.04), and in former smokers with a history of fewer than 10 pack-years (trial 1, P = 0.14; trial 2, P = 0.047) in post hoc analysis. However, improvements were independent of other factors that were analyzed, including geographic region, level of reversibility, age (post hoc), body-mass index, allergic status, asthma duration, ACQ-7 score at baseline, and use of systemic glucocorticoids in the year before trial enrollment. Similar results were observed in the analysis of the time to the first severe exacerbation

Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype H. Iwamoto Eur Respir J 2008; 31: 1379–1382 17 ağır astım İKS 17 (%100) Oral steroid 4 (%23.5) LABA 11 (%64.7) Theophylline 6 (%35.3) LTRA 11 (%64.7) 4 hafta Tiotropium FEV1 de anlamlı düzelme (p=0.001)

Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype H. Iwamoto Eur Respir J 2008; 31: 1379–1382 : smokers : nonsmokers

FEV1 de ≥%15 (veya 200 ml) artış Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response H.W. Park Allergy 2009: 64: 778–783 138 ağır astım İKS+LABA 138 (%100) LTRA 56 (%40) Theophylline 32 (%23) Oral steroid 12 (%9) 8 hafta Tiotropium 18 μg Responder FEV1 de ≥%15 (veya 200 ml) artış (n:46 %33)

Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response H.W. Park Allergy 2009: 64: 778–783 This study demonstrates that as many as 30% of severe asthmatics treated with a combination of high-dose inhaled corticosteroid and long-acting b2 agonist responded to the addition of tiotropium. The exacerbation rate for 143 patients (excluding 17 patients who were noncompliant and withdrew enrollment) in this study was 1.4 events/100 patients/year. Meanwhile, the exacerbation rate of the same asthmatics in the preceding year (based on the review of medical records) was 48.2 events/100 patients/year. Exacerbation rate was not a primary outcome and thus the present study was not powered to evaluate effect of tiotropium on exacerbations. However, a dramatic fall in exacerbation rate suggested a probable role of tiotropium additive to lung function improvement.

Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis Jing-wei TIAN, Respir Care 2013 in press Change in morning PEF Change in evening PEF

Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis Jing-wei TIAN, Respir Care 2013 in press Change in peak FEV1 Change in peak FVC

Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis Jing-wei TIAN, Respir Care 2013 in press Total adverse events Serious adverse events

Kanıt düzeyi yüksek değil SONUÇ: Kanıt düzeyi yüksek değil Çalışma sayısı az Hasta sayısı az Çalışma süreleri kısa (4,14,16,18,48 hafta)

Yanıtlanmamış sorular var Astım atağına etkisi? Hangi hastalarda daha etkili? Çocuk ve ergenlerde kullanılır mı? Fiks obstrüksiyonu olan hastada etkili mi? Güvenli mi?

Yürütülmekte olan veya sonuçları henüz yayınlanmamış Astım-Tiotropium çalışmaları www.clinicaltrials.gov Çalışma No Yaş Astım ağırlığı Tedavi NCT01316380 Erişkin Hafif İCS’ye ek NCT01172808 Orta İCS+LABA’ya ek NCT01172821 NCT01257230 Adölesan (12-17 yaş) Kullandığı tedaviye ek NCT01277523 Ağır NCT01634139 Çocuk (6-11 yaş) NCT01634152

UniTinA-asthma™ Phase III trial programme ongoing The PrimoTinA-asthma studies are part of Boehringer Ingelheim's comprehensive ongoing Phase III trial programme named UniTinA-asthma, which was designed to establish the efficacy and safety of tiotropium, delivered by the Respimat Soft Mist Inhaler (SMI) in patients with asthma. UniTinA-asthma includes trials in adults, adolescents and children and involves over 4,000 patients in more than 150 sites globally.  Included in the UniTinA-asthma umbrella programme are the following studies: PrimoTinA-asthma™ Adult study - 205.416/.417 [4;5] (Kersjten atak)    NCT00772538 , NCT00776984  MezzoTinA-asthma™ Adult study - 205.418/.419 [6;7] NCT01172808 , NCT01172821 GraziaTinA-asthma™ Adult study - 205.442 [8]     NCT01316380   VivaTinA-asthma™ Paediatric study - 205.445/.446 [9;10]   NCT01634139 , NCT01634152  RubaTinA-asthma™ Adolescent study - 205.444 [11]     NCT01257230 PensieTinA-asthma™ Adolescent study - 205.456 [12]     NCT01277523 TALC NCT00565266 Bateman NCT00350207 Kersjten Tio improves lung function NCT00365560

A) PrimoTinA-asthma™ Adult study - 205.416/.417 [4;5]  Kersjten atak  NCT00772538 , NCT00776984  B) MezzoTinA-asthma™ Adult study - 205.418/.419 [6;7] These studies have been completed. 1- Evaluation of Tiotropium 2.5 and 5 Mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 Mcg Twice Daily) in Patient With Moderate Persistent Asthma I NCT01172808 2- Evaluation of Tiotropium 2.5 and 5 Mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 Mcg Twice Daily) in Patient With Moderate Persistent Asthma II NCT01172821. The aim of these trials is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium over a 24-week treatment period as compared to placebo and salmeterol (50 mcg twice daily). Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on quality of life, effects on asthma control, effects on health care resource utilisation, and number of adverse events.

C) GraziaTinA-asthma™ Adult study - 205 C) GraziaTinA-asthma™ Adult study - 205.442 [8]     This study has been completed. 1- Efficacy and Safety of 2 Doses of Tiotropium Via Respimat in Adult Patients With Mild Persistent Asthma NCT01316380 The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers of adverse events. D) VivaTinA-asthma™ Paediatric study - 205.445/.446 [9;10]   This study is currently recruiting participants. 1- Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Moderate Persistent Asthma NCT01634139 The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily in the evening) over 48 weeks, compared to placebo, in children (6 to 11 years old) with moderate persistent asthma. 2- Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Severe Persistent Asthma NCT01634152  This study is currently recruiting The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution (2.5 mcg and 5 mcg) delivered via Respimat® inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.

E) RubaTinA-asthma™ Adolescent study - 205 E) RubaTinA-asthma™ Adolescent study - 205.444 [11]   This study has been completed.  Efficacy and Safety of 2 Doses of Tiotropium Via Respimat Compared to Placebo in Adolescents With Moderate Persistent Asthma NCT01257230 The aim of the study is to evaluate efficacy and safety of a 48-week treatment with two doses of tiotropium bromide compared to placebo in adolescent patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring lung function parameters and evaluating the effects on asthma exacerbations, on Quality of life, on health care resource utilisation an on the number of adverse events. F) PensieTinA-asthma™ Adolescent study - 205.456 [12]    This study has been completed.  Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents With Severe Persistent Asthma NCT01277523 The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily) over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma. The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment. Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population.