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Leonardo M. Fabbri fabbri.leonardo@unimo.it

12th Annual Congress of the Turkish Thoracic Society Antalya 8 -12 April 2009. http//pneumologia.unimo.it. Sungate Port Royal Beldibi, Antalya 9 April 2009. Combination Therapy in Asthma. Leonardo M. Fabbri fabbri.leonardo@unimo.it.

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Leonardo M. Fabbri fabbri.leonardo@unimo.it

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  1. 12th Annual Congress of the Turkish Thoracic Society Antalya 8-12 April 2009 http//pneumologia.unimo.it Sungate Port Royal Beldibi, Antalya 9 April 2009 Combination Therapy in Asthma Leonardo M. Fabbri fabbri.leonardo@unimo.it

  2. EUROPEAN RESPIRATORY SOCIETYYEAR OF THE LUNG 2009-2010 Shaping the Future of Respiratory Medicine in Europe Leonardo M. Fabbri ERS Past-President fabbri.leonardo@unimo.it

  3. Berlin 2008 - Registration Please refer to pages 29 -30 of the Guidelines for detailed figures 19’356 participants Biggest Respiratory Congress in the World

  4. Berlin 2008 - Audience Congress attendance – Top 26 countries

  5. ERS Annual Congress

  6. ERS Membership

  7. Turkish Members * Introduction of the Joint Membership

  8. 12th Annual Congress of the Turkish Thoracic Society Antalya 8-12 April 2009 http//pneumologia.unimo.it Sungate Port Royal Beldibi, Antalya 9 April 2009 Combination Therapy in Asthma Leonardo M. Fabbri fabbri.leonardo@unimo.it

  9. COMBINATION THERAPY IN ASTHMA Leonardo M. Fabbri Persistent asthma may not require regular treatment Definition of control requires revision Role of asthmatic inflammation and its suppression remains to be established LABA/ICS combination for mantainance and reliever therapy is the most effective treatment of persistent asthma

  10. Management of asthma in untreated patients, GINA guidelines, 2008 Mild Intermittent Avoidance of risk factors, immunotherapy Fast-acting beta-2 agonists as needed Mild Persistent Low-dose inhaled steroids Asthma severity Clinical Features Before Treatment Combination of long-acting beta2 agonists with low dose inhaled steroids Moderate Persistent Moderate Persistent (Severe?) Combination with higher doses inhaled corticosteroids, theophylline, antileukotrienes Severe Persistent (Very severe?) Systemic steroids Anti-IgE

  11. GINA Guidelines 2008 www.ginasthma.org

  12. LEVEL OF CONTROL TREATMENT OF ACTION REDUCE maintain and find lowest controlling step controlled consider stepping up to gain control partly controlled uncontrolled step up until controlled INCREASE exacerbation treat as exacerbation REDUCE INCREASE TREATMENT STEPS STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

  13. Levels of Asthma Control

  14. GINA Guidelines 2008 www.ginasthma.org

  15. mast cells 760 720 240 200 160 120 80 40 0 Pre-BD 6 wk Pre-BD 6 wk Pre-BD 6 wk Effects of Inhaled Beclomethasone Dipropionate in Clinical Asthma Bronchial Function Bronchial Submucosa PC20 methacholine (mg/ml) Asthmatic symptoms eosinophils T lymphocytes number of cells/mm2 of submucosa Severity mg/ml Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74

  16. RESCUE USE OF BECLOMETHASONE AND ALBUTEROL IN A SINGLE INHALER FOR MILD ASTHMA In patients with mild asthma, the symptom-driven use of inhaled beclomethasone/albuterol combination in a single inhaler is as effective as regular use of inhaled beclomethasone and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid Papi et al, N Engl J Med 356; 2040-2052 (May 17, 2007)

  17. Study design Twice daily inhaled placebo plus p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination Twice daily inhaled placebo plus p.r.n. inhaled 100 µg salbutamol Beclomethasone (500µg/day) Twice daily inhaled 250 µg beclomethasone plus p.r.n. 100 µg salbutamol Twice daily inhaled 250 µg beclomethasone/100 µg salbutamol combination plus p.r.n. inhaled 100 µg salbutamol Visit 1 (screening) Visit 2 (randomization) Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 (end of treatment) 4-Week Run-in Period 6-month Treatment Period Papi A et al. N Engl J Med 2007;356:2040-52

  18. * * * Missing Values Replaced with the Use of LOCF 460 Baseline Weeks 5-6 Weeks 11-12 Weeks 17-18 Weeks 22-24 440 * 420 Morning PEF (liters/min) 400 380 360 prn BDP/S prn S regular BDP regular BDP/S Papi A et al. N Engl J Med 2007;356:2040-52

  19. EFFECT OF EXACERBATIONS 2 1,5 Number of exacerbations per patients/year 1 0,5 0 As needed As needed Regular Regular combination albuterol beclomethasone combination Papi A et al. N Engl J Med 2007;356:2040-52 Papi A et al. N Engl J Med 2007;356:2040-52

  20. CUMULATIVE DOSE OF BECLOMETHASONE (BDP) ** ** 100 80 60 mg 40 20 0 prn BDP/S prn S regular BDP regular BDP/S Papi A et al. N Engl J Med 2007;356:2040-52

  21. REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN Papi et al, submitted, 2008

  22. REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN Papi et al, submitted, 2008

  23. REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN Regular beclomethasone but not prn beclomethasone/salbutamol combination increased the percentage of symptom-free days and reduced exacerbations. However, prn combination was effective on most secondary outcomes, convenient and potentially safer; thus we suggest that it should be explored further Papi et al, submitted, 2009

  24. IMPORTANCE OF INFLAMMATION IN ASTHMA: pathology of asthma death Fig. 5 Quadro anatomo-patologico di un soggetto morto per asma bronchiale

  25. COPD Asthma B A B D C Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-424

  26. GINA Guidelines 2008 www.ginasthma.org

  27. Changes in FEV1 during the study 90 85 FEV1 (% of predicted) 80 75 Higher-dose budesonide plus formoterol Lower-dose budesonide plus formoterol Higher-dose budesonide Lower-dose budesonide -1 0 1 2 3 6 9 12 Month Pauwels RA et al., N Engl J Med 1997 FACET

  28. Estimates of severe exacerbation rates BUD200 h=0.91 BUD800 h=0.46 BUD200+F h=0.67 BUD800+F h=0.34 BUDH: - 49% (p<0.001) p=0.031 FORM: - 26% (p=0.014) Pauwels RA et al., N Engl J Med 1997

  29. Modulite: extrafine formulations

  30. BDP/FF extrafine combination clinical evidence BDP/FF vs separate components 6-month study BDP/FF vs. BDP + FF in separate inhalers vs. BDP alone 3-month study BDP/FF vs. BDP alone BDP/FF vs available ICS/LABA fixed combinations 3-month studies BDP/FF Vs. Budesonide/formoterol BDP/FF vs. Fluticasone/salmeterol

  31. First Pivotal Study: BDP/FF extrafine combination vs BDP CFC + formoterol DPI vs BDP CFC Huchon G, Resp Med 2009

  32. BDP/FF extrafine combination versus the separate components and BDP CFC non extrafine BDP/FF extrafine combination total daily dose of 400 µg extra fine BDP and 24 µg formoterol BDP CFC +formoterol DPI (separate inhalers) total daily dose of 1000 µg non-extrafine BDPand24 µg formoterol 2-weeks RUN IN BDP CFC total daily dose of 1000 µg non-extrafine BDP 6 MONTHS • 645 moderate-to-severe asthmatic patients • ICS at entry: 750-1000 µg BDP or equivalent • Mean FEV1 at baseline (% predicted normal) : 64.5%-66.2%

  33. BDP/FF extrafine combination shows similar improvement in morning PEF (PRIMARY ENDPOINT) compared to the separate components, and a better outcome compared to BDP alone BDP 1000µg CFC BDP/FF extrafine combination 400/24 µg BDP CFC+formoterol 1000/24 µg 380 360 340 # * Morning PEF (L/min) 320 300 *p<0.001 vs baseline 280 # NS between treatments 260 0 4 8 12 16 20 24 Time (weeks)

  34. % days free of clinical symptoms p < 0.05 35 30 25 20 Percentage 15 10 5 0 BDP CFC +formoterol 1000/24 µg BDP/FF 400/24 µg BDP 1000 µg CFC BDP/FF extrafine combination was significantly superior to the separate components and to BDP monotherapy with relation to clinical measures of asthma control

  35. N. of overall exacerbations N. of severe exacerbations 2.02 1.6 * p<0.05 vs. BDP 1000µg CFC 1.33* 0.75 0.66 0.45* BDP/FF extrafine combination demonstrated to be effective in reducing asthma exacerbations 2.4 2 1.6 N. of exacerbations per patient 1.2 0.8 0.4 0 BDP CFC+ formoterol 1000/24 µg BDP 1000 µg CFC BDP/FF 400/24 µg

  36. BDP/FF extrafine combination: lack of cortisol suppression Morning Serum Cortisol (nmol/L) Changes from Baseline to week 24 -Means and 95% CI- * 200 150 100 50 Morning Serum Cortisol (nmol/L) Changes from Baseline to week 24 0 -50 -100 -150 BDP CFC+ formoterol 1000/24 µg BDP/FF 400/24µg BDP 1000 µg CFC -200

  37. BDP/FF extrafine combination versus the separate components and BDP CFC non extrafine Summary • Similar improvement in morning PEF and FEV1, compared to the single drugs administered separately and superiority of BDP/FF fixed combination versus BDP CFC monotherapy on the same parameters • Superiority of BDP/FF fixed combination compared to BDP monotherapy, with relation to exacerbation frequency • Lack of cortisol suppression with BDF/FF as a consequence of a reduced steroid exposure • Superiority in some parameters of 1 vs 2 inhalers

  38. BDP/FF extrafine combination clinical evidence BDP/FF vs separate components 6-month study BDP/FF vs. BDP + FF in separate inhalers vs. BDP alone 3-month study BDP/FF vs. BDP alone BDP/FF vs available ICS/LABA fixed combinations 3-month studies BDP/FF Vs. Budesonide/formoterol BDP/FF vs. Fluticasone/salmeterol

  39. Inhaled Combination Asthma Treatment (ICAT) studies ICAT SY DAILY DOSES: BDP/FF extrafine combination: 400 µg BDP + 24 µg formoterol Vs. Budesonide/formoterol 800 µg BUD + 24 µg formoterol ICAT SE DAILY DOSES: BDP/FF fixed combination 400 µg BDP + 24 µg formoterol Vs Fluticasone/salmeterol 500 µg fluticasone + 100 µg salmeterol

  40. Randomized, double blind, double dummy, multinational, parallel-group design study comparing BDP/FF extrafine combination with budesonide/formoterol in a 3 months treatmentof moderate to severe asthmatic patients ICAT SY. BDP/FF extrafine combination vs. budesonide/formoterol combination • 216 moderate-to-severe asthmatic patients • ICS at entry:  1000 µg BDP or equivalent • Mean FEV1 at baseline (% predicted normal) : 69.3%-70.5% Papi A, Paggiaro PL, Vignola AM, NIcolini G, Fabbri LM.ERJ 2007

  41. ICAT SY. Study Design BDP/FF extrafine combinationdaily dose 400 µg BDP + 24 µg formoterol 12 weeks Run in 2 weeks Budesonide/formoteroldaily dose 800 µg BUD+24 µg formoterol 12 weeks 4 weeks 4 weeks 4 weeks Visit 1 Screening Visit 2 Randomization Visit 3 Visit 4 Visit 5 Visit 6 end of treatment

  42. ICAT SY. Morning PEF Comparable improvement for both BDP/FF extrafine combination and budesonide/formoterol BDP/FF extrafine combination 400/24 µg Budesonide/formoterol 800/24 µg 350 * * # * * * 340 * 330 * * * * * * 320 L/min 310 300 *p<0.001 vs baseline 290 # NS between treatments 280 Baseline 4 8 12 Weeks

  43. ICAT SY. Asthma symptom score Comparable effects of BDP/FF extrafine combination vs budesonide/formoterol at day and night-time Daytimeasthma symptom score Night-time asthma symptom score 2.0 2.0 1.5 1.5 * * * * * # * * * Symptom score Symptom score 1.0 1.0 * * * # * * * * * * * * * 0.5 0.5 * * * * 0 0 Baseline 4 8 12 Baseline 4 8 12 Weeks Weeks BDP/FF extrafine combination 400/24 µg *p<0,001 vs baseline NS between treatments # Budesonide/formoterol 800/24 µg

  44. BDP/FF extrafine combination improves lung function similarly to budesonide/formoterol with half the dose of inhaled corticosteroid BDP/FF extrafine combination demonstrated to be not significantly different from budesonide/formoterol also in terms of asthma symptoms reduction and exacerbation rate ICAT SY. BDP/FF extrafine combination vs. budesonide/formoterol combination Summary

  45. Inhaled Combination Asthma Treatment (ICAT) studies ICAT SY DAILY DOSES: BDP/FF extrafine combination: 400 µg BDP + 24 µg formoterol Vs. Budesonide/formoterol 800 µg BUD + 24 µg formoterol ICAT SE DAILY DOSES: BDP/FF fixed combination 400 µg BDP + 24 µg formoterol Vs. Fluticasone/salmeterol 500 µg fluticasone + 100 µg salmeterol

  46. ICAT SE.BDP/FF extrafine combination versus fluticasone/salmeterol combination Randomized, double blind, double masking, multinational, parallel-group design study comparing BDP/FF extrafine combination with fluticasone/salmeterol in the 3 months treatment of moderate to severe asthmatic patients • 216 moderate-to-severe asthmatic patients • ICS at entry:  1000 µg BDP or equivalent • Mean FEV1 at baseline (% predicted normal) : 66.9%-67.6% Papi A*, Paggiaro PL*, Vignala AM, Nicolini G, Fabbri LM. Allergy 2007

  47. ICAT SE. Study Design BDP/FF extrafine combinationdaily dose 400 µg BDP + 24 µg formoterol 12 weeks Run in 2 weeks fluticasone/salmeteroldaily dose 500 µg FP + 100 µg salmeterol 12 weeks 4 weeks 4 weeks 4 weeks Visit 1 Screening Visit 2 Randomization Visit 3 Visit 4 Visit 5 Visit 6 end of treatment

  48. ICAT SE. Morning PEF comparable improvement for both BDP/FF extrafine combination and fluticasone/salmeterol BDP/FF extrafine combination 400/24 µg Fluticasone/salmeterol 500/100 µg 350 * * # * * 340 * * 330 * 320 * * * * 310 * L/min 300 290 280 270 *p<0.001 vs baseline 260 # NS between treatments 250 Baseline 4 8 12 Weeks

  49. ICAT SE. Asthma symptom score Comparable effects of BDP/FF extrafine combination and fluticasone/salmeterol at day and night-time Daytimeasthma symptom score Night-time asthma symptom score 2.0 2.0 1.5 1.5 * Symptom score Symptom score * * 1.0 1.0 * * * * * * # * * * # * * * 0.5 0.5 * * * * * * * * * 0 0 Baseline 4 8 12 Baseline 4 8 12 Weeks Weeks BDP/FF extrafine combination 400/24 µg *p<0,001 vs baseline NS between treatments # Fluticasone/salmeterol 500/100 µg

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