1. Analysis of chronic obstructive pulomnary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study Lancet Respir Med 2013;1:199-209 Jadwiga A Wedzicha, Marc Decramer, Joachim H Ficker, Dennis E Niewoehner, Thomas Sandstrom, Angel Fowler Taylor, Peter D’Andrea, Christie Arrasate, Hungta Chen, Donald Banerji R3 변자민

2. BACKGROUND COPD acute exacerbation (AE) -Associated with poor prognosis -Prevention of AE: key objective for new drug treatment Long-acting inhaled bronchodilators (LABAs & LAMAs): mainstay tx of COPD AE prevention QVA149: LABA indacaterol 110 μg+ LAMA glycopyrronium 50 μg

3. BACKGROUND Purpose: To evaluate the effect of once-daily QVA on exacerbations of COPD in patients with severe or very severe airflow limitation, and to compare its effect with the once-daily LAMAs glycopyrronium and tiotropium

4. METHODS Study design -SPARK: 362 centers, 27 countries -Pre-randomization period + double-blind, parallel-group treatment period (64 ~ 76 weeks) -Patients randomly assigned (1:1:1) to receive QVA149, glycopyrronium, tiotropium -Patients completed e-dairy every morning and followed up every 2 weeks -Spirometry and health status (St George ’ s Respiratory Questionnaire) done at baseline and at clinic visits

5. METHODS Patients Inclusion CriteriaExclusion Criteria GOLD stage III or IV COPD AE requiring hospitalization in the 6 weeks before pre-screening or during screening History of at least one exacerbation in the pervious 12 months requiring treatment with systemic corticosteroids and/or antibiotics COPD AE development during pre- screening or screening Either current smoker or ex- smoker 10 or more pack-years of smoking history Hx of respiratory tract infection within 4 weeks before pre-screening

6. METHODS Objectives, assessments & outcome measures -Primary objective: demonstrate superiority of QVA149 compared with glycopyrronium for moderate or severe COPD AE -Secondary objective: demonstrate superiority of QVA149 compared with tiotropium, compare effect of QVA149 vs. glycopyrronium and tiotropium on bronchodilator effect and use of rescue salbutamol during the treatment period -Definition of COPD AE: worsening of symptoms (as recorded on e diaries) ① Mild: self-manageable ② Moderate: require systemic corticosteroids and/or antibiotics treatment ③ Severe: require hospitalization or emergency treatment

7. METHODS Randomization & masking Randomization: stratified by current or ex-smoker status and inhaled corticosteroid use Unmasking: in case of emergency & at conclusion Treatments: every monring 8 AM ~ 11AM -QVA149 (indacaterol 110μg+ glycopyrronium 50μg) vs. Glycopyrronium 50μg vs. Tiotropium 18μg -p.r.n salbutamol Statistical analysis Role of the funding source

8. RESULTS

9. 75% completed the study

11. 32 patients (1%) did not experience AE

12. 15% reduction14% reduction

13. p =0.0052 p =0.0072 p =0.096 p =0.038 p =0.36 p =0.18 p =0.0017 p =0.0012

14. p < 0.0001

15. Figure 4: (A)SGRQ total scores during treatment (B)percentages of patients achieving the minimum clinically important difference (≥4 units) in SGRQ score *QVA149 versus glycopyrronium; †QVA149 versus tiotropium

17. Table 5: Serious adverse events (SAEs), including COPD exacerbations, by primary system organ class and preferred term (occurring in ≥0.5% of any treatment group) Patient deaths: 23 (3%) vs.22 (3%) vs.25 (3%) COD: ① COPD worsening ② Cardiorespiratory arrest

18. DISCUSSION The first report of the efficacy of dual long-acting bronchodilator treatment in a population of patients with severe and very severe COPD at high risk of COPD exacerbations The study met its primary endpoint: QVA149 significantly reduced the rate of moderate to severe exacerbations by 12% compared with glycopyrronium, and by 10% compared with tiotropium

19. DISCUSSION Treatment with QVA149 would clearly be of key importance in the management of COPD -to prevent exacerbations -to try to prevent progression over time in the severity of exacerbation ① exacerbations needing treatment become more common as COPD becomes more severe ② one severe exacerbation is followed at increasingly shorter intervals by the next severe exacerbation and, ultimately, death

20. DISCUSSION Limitations 1)Tiotropium was administered open label a.Tiotropium is a hygroscopic powder and cannot be repacked into unmarked capsules b.For legal reasons, a third party cannot manufacture fully matching placebo capsules 2)Because the present study was undertaken across a wide geographical area, factors such as ethnicity and region might have influenced results

21. CONCLUSIONS 1.The enhanced bronchodilator effect of QVA149 translated into a greater efficacy in preventing moderate to severe exacerbations of COPD compared with treatment with the single LAMA glycopyrronium in patients with severe and very severe COPD. 2.The bronchodilator effect of QVA149 treatment was associated with an increased improvement in health status. 3.QVA149 was safe and well tolerated and has a safety profile similar to that of the single agents.