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

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... konulu sunumlar: "Astım tedavisinde Tiotropium’un yeri Dr. Haluk Türktaş Gazi Üniversitesi Ankara."— Sunum transkripti:

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

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

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

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

5 n:18 Ağır astım İCS FP 1000 μg SFT 4 hafta FP 500+SALM+Plasebo Crossover FP 500+SALM+Tiotropium Stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma Tom Fardon Respir Med 2007: 101; 1218–1228

6 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 PEF41 L/dk FEV10.11 L RAW-%33 Salmeterol +Tiotropium eklenmesi ile sağlanan düzelmeler Sabah PEF55L/dk FEV10.17 L RAW-%34 FeNO-2.86 ppb Düzelme sağlanamayanlar TLC veya RV Semptom, yaşam kalitesi

7 n:210 Hafif-orta astım İCS BDP 160 μg ICS+Tiotropium (18 μg ) FEV 1 PEF Astım kontrol 14 hafta ICS+Salmeterol (2x50μg) İki kat doz BDP (320 μg) Crossover 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

8 Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma NHLBI Asthma Clinical Research Network N Engl J Med 2010;363:1715-26

9 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

10 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

11 n:107 Yüksek doz İCS+LABA Kontrolsüz ağır astım Tiotropium (5μg ) FEV 1 8 hafta Tiotropium (10μg) Plasebo Crossover 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

12 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

13 n:912 İCS+LABA Kontrolsüz astım İCS+LABA+Plasebo İCS+LABA+Tiotropium (5μg) SFT Atak 48 hafta Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207

14 Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207 İlk ağır atak için geçen süre: 282 vs 226 gün Risk reduction %21 (p=0.03) 86 ml 154 ml All on top of ICS+LABA

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

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

17 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

18 Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens N Engl J Med 2012;367:1198-207 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 Altgrup Analizleri

19 Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype H. Iwamoto Eur Respir J 2008; 31: 1379–1382 17 ağır astım İKS17 (%100) Oral steroid 4 (%23.5) LABA 11 (%64.7) Theophylline 6 (%35.3) LTRA11 (%64.7) 4 hafta Tiotropium FEV1 de anlamlı düzelme (p=0.001)

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

21 138 ağır astım İKS+LABA138 (%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

22 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

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

24 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

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

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

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

28 Çalışma NoYaşAstım ağırlığıTedavi NCT01316380ErişkinHafifİCS’ye ek NCT01172808ErişkinOrtaİCS+LABA’ya ek NCT01172821ErişkinOrtaİCS+LABA’ya ek NCT01257230Adölesan (12-17 yaş) OrtaKullandığı tedaviye ek NCT01277523Adölesan (12-17 yaş) AğırKullandığı tedaviye ek NCT01634139Çocuk (6-11 yaş) OrtaKullandığı tedaviye ek NCT01634152Çocuk (6-11 yaş) AğırKullandığı tedaviye ek Yürütülmekte olan veya sonuçları henüz yayınlanmamış Astım-Tiotropium çalışmaları www.clinicaltrials.gov

29

30 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 NCT00772538NCT00776984 MezzoTinA-asthma™ Adult study - 205.418/.419 [6;7] NCT01172808, NCT01172821 NCT01172808NCT01172821 GraziaTinA-asthma™ Adult study - 205.442 [8] NCT01316380 NCT01316380 VivaTinA-asthma™ Paediatric study - 205.445/.446 [9;10] NCT01634139, NCT01634152 NCT01634139NCT01634152 RubaTinA-asthma™ Adolescent study - 205.444 [11] NCT01257230 NCT01257230 PensieTinA-asthma™ Adolescent study - 205.456 [12] NCT01277523 NCT01277523 TALC NCT00565266 Bateman NCT00350207 Kersjten Tio improves lung function NCT00365560

31 A) PrimoTinA-asthma™ Adult study - 205.416/.417 [4;5] Kersjten atak NCT00772538 NCT00772538, NCT00776984 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 NCT01172808NCT01172808 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.NCT01172821

32 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 NCT01316380NCT01316380 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 NCT01634139NCT01634139 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 recruitingNCT01634152 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.

33 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 NCT01257230NCT01257230 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 NCT01277523NCT01277523 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.


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