1. N Engl J Med 2012 ; 367 : 1198-1207. Huib A.M. Kerstjens, M.D., Michael Engel, M.D., Ronald Dahl, M.D., Pierluigi Paggiaro, M.D., Ekkehard Beck, M.D., Mark Vandewalker, M.D., Ralf Sigmund, Dipl.Math., Wolfgang Seibold, M.D., Petra Moroni-Zentgraf, M.D., and Eric D. Bateman, M.D. Journal conference R2 Seon-Hye Kim, Prof. Hong-Mo Kang

2. BACKGROUND : Poorly controlled asthma  Recurring symptoms and exacerbations despite the use of preferred controller drugs (i.e., inhaled glucocorticoids ± inhaled long-acting beta-agonists [LABAs]).  Adding a long-acting anticholinergic bronchodilator (tiotropium)  Not been evaluated in long-term clinical trials

3. EVALUATION (PrimoTinAasthma 1 & 2 trials) : the efficacy & safety of adding tiotropium as compared with placebo, to a treatment regimen of glucocorticoids and LABAs. Long-acting anticholinergic bronchodilator: Tiotropium : the most widely used long-acting bronchodilator worldwide for the treatment of COPD.

4. Inclusion criteria  Age : 18 yrs and 75 yrs  ≥ 5yrs Hx. of asthma & diagnosed before the age of 40yrs.  Post-bronchodilator FEV1 <80% or FVC<70% + ICS & LABAs  ≥ 1 exacerbation in the previous year + systemic glucocorticoids  Non-smokers or < 10PY smoking Hx Exclusion criteria  Past diagnosis of COPD  Serious co-existing illnesses  Concurrent use of anticholinergic bronchodilators

5. PrimoTinAasthma 1 & 2 trials 2 replicate trials : Randomized, double-blind, placebo-controlled, parallel-group design. Duration : 48-week study period Multicenter trial : Australia, Canada, Denmark, Great Britain, Germany, Italy, Japan, Taiwan, The Netherlands, New Zealand, Serbia, South Africa, Turkey. 5 μg of tiotropium or matching placebo each morning add-on therapy to individual pre-trial maintenance asthma therapy consisting of high-dose ICS & LABAs.

6. Primary end points 1) peak FEV1 response 2) trough FEV1 response 3) time to the 1st severe asthma exacerbation (need systemic glucocorticoid) Secondary efficacy outcome 1) peak FEV1 & FVC at each treatment visit 2) trough FEV1 & FVC at each treatment visit 3) time to the 1st worsening of Asthma ( Sx ↑ or decline of >30% PEF)

12. 56 days

16. Tiotropium : In patients with poorly controlled asthma despite treatment with inhaled glucocorticoids and LABAs, adding tiotropium significantly reduced the risk of episodes of the worsening of asthma and asthma exacerbations and provided sustained bronchodilation.