2. New decade, New approaches to AECOPD Prof. Nadeem Rizvi Head of Chest Medicine Jinnah Postgraduate Medical Center, Karachi

3. Definition of COPD Exacerbations An event in the natural course “of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.” From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org. 2

4. Social withdrawal Worsening quality of life More exacerbations Increased risk of hospitalisation What Does an Exacerbation Mean to a Patient? Greater anxiety Decline in lung function Garcia-Aymerich J et al. 2001 Donaldson D et al. 2002 Gore JM et al. 2000 Seemungal T et al. 1998 Pauwels Pet al. 2001 Seemungal T et al. 2000 Garcia-Aymerich J et al. 2003 Anto JM et al. 2001 Increased symptoms (I.e. breathlessness) Increased risk of mortality

5. Causes of AECB Ball. CHEST 1995; 108: 43S–52S; Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications, 2004; Donaldson et al. Eur Respir J 1999; 13: 844–9 AECB Weather Fall in temperature Infection Bacterial Viral Allergy Pollution Cigarette smoke Industrial dusts

6. Epidemiology of Exacerbations: Frequency Increases with Declining FEV 1 Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168. FEV 1 (1) 2.5 2.0 0.5 0 < 1.251.25 – 1.54> 1.542.40 3.0 1.5 Exacerbations per Year 2.50 1.0 5

7. Impact of Exacerbations in COPD Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796. Patients with Frequent Exacerbations Higher Mortality Faster Decline in Lung Function Poorer Quality of Life Greater Airway Inflammation 6

8. More Rapid Decline in FEV 1 With Higher Exacerbation Frequency Donaldson GC, et al. Thorax. 2002;57:847-852. Years 0.90 0.75 0 0.95 0.85 Percent Change from Baseline in FEV 1 0.80 1234 Infrequent Exacerbators Frequent Exacerbators 7

9. Frequent Exacerbations Are Associated With More Rapid Decline in Pulmonary Function * FEV 1 (mL)PEF (L/minute) Annual Change ** * P<0.05 versus infrequent exacerbators; ** P<0.001 versus infrequent exacerbators Donaldson GC, et al. Thorax. 2002;57:847-852. 8

10. Daily Median PEFR as % Baseline Pulmonary Function Recovers Slowly After an Exacerbation Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613. Days 100 99 96 95 -14 101 98 97 -9-4161116212631 Exacerbation 9

11. Mortality Following Emergency Department Visit for COPD Exacerbation Kim S, et al. COPD. 2006;3:75-81. 10

12. Exacerbation Frequency and Severity Both Increase Mortality Risk Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931. Group Apatients with no acute exacerbations Group Bpatients with 1–2 acute exacerbations requiring hospital management Group Cpatients with >3 acute exacerbations Group (1)no acute exacerbations Group (2)acute exacerbations requiring emergency service visits without admission Group (3)patients with acute exacerbations requiring one hospital admission Group (4)patients with acute exacerbations requiring readmissions 1.0 0.8 0.6 0.4 0.2 0.0 0102030405060 Time (months) A p<0.0002 B p=0.069 C p<0.0 Probability of surviving 1.0 0.8 0.6 0.4 0.2 0.0 0102030405060 Time (months) (1) (3) (4) Probability of surviving p<0.0001 (2) NS p=0.005 p<0.0001 11

13. Cost of Treatment for an Acute Exacerbation of COPD O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120. 123

15. Exacerbations Negatively Affect Quality of Life Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613. * P<0.05 versus lower exacerbation rate * * * * 14

17. ISSUE OF ANTIBIOTIC USE IN EXACERBATION

19. Stratification of AECB patients – the Anthonisen criteria Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Eur Respir J 2005] Increase in: dyspnea sputum volume sputum purulence TYPE I All three present, antibiotic recommended TYPE II Two of three present, antibiotic recommended if includes purulence TYPE III One of three present, antibiotic not recommended

23. Using Antibiotics in AECB Prevents Treatment Failure Relative Risk (95% Confidence Interval) Pooled summary (RR, 0.54; 95% CI, 0.32-0.92) Elmes et al, 1965 Pines et al, 1968 Anthonisen et al, 1987 Jorgensen et al, 1992 Nouira et al, 2001 100.10.20.5251 Favours PlaceboFavours Antibiotics Quon BS et al. Chest 2008; 133:756-766 Treatment failure is associated with increased acute exacerbation episodes and disease progression

24. 23

26. Bacterial pathogens isolated from sputum in recent studies of acute exacerbations of chronic bronchitis Sethi. Clin Infect Dis 2005; 40: S489–97 Data are mean (range) percentage of total bacterial isolates Number of patients: 687 (140–2180) Sputum culture positive for potentially pathogenic bacteria: 53.7 (28.1–88.6) Gram-positive pathogens Gram-negative pathogens Enteric pathogens 11.4% (3–19) P. aeruginosa 5.8% (1–13) H. parainfluenzae 9.4% (0–32) M. catarrhalis 14.0% (4–21) Non-typeable H. influenzae 31.2% (13–50) S. aureus 6.4% (1–20) S. pneumoniae 14.2% (7–26)

27. Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim–sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class MILD Only 1 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence Fluoroquinolone (moxi, gemi, levo) Amoxicillin-clavulanate If at risk for Pseudomonas, consider ciprofloxacin and obtain sputum culture If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence A wind of change in AECOPD Antibiotics for AECOPD: Risk Stratification No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Reevaluate Consider sputum culture Worsening clinical status or inadequate response in 72 hrs Sethi S, Murphy TF. NEJM 2008;359:2355-65.

28. Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim–sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class Reevaluate Consider sputum culture MILD Only 1 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence Fluoroquinolone (moxi, gemi, levo) Amoxicillin-clavulanate If at risk for Pseudomonas, consider ciprofloxacin and obtain sputum culture If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence A wind of change in AECOPD No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Worsening clinical status or inadequate response in 72 hrs Antibiotics for AECOPD: Risk Stratification Sethi S, Murphy TF. NEJM 2008;359:2355-65.

29. Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease Advanced macrolide (azythromycin, clarithromycin) Cephalosporin (cefuroxime, cefpodoxime, cefdinir) Doxycycline Trimethoprim–sulfamethoxazole If recent antibiotic exposure (<3 months), use alternative class MILD Only 1 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence Fluoroquinolone (moxi, gemi, levo) Amoxicillin-clavulanate If at risk for Pseudomonas, consider ciprofloxacin and obtain sputum culture If recent antibiotic exposure (<3 months), use alternative class MODERATE OR SEVERE At least 2 of the 3 cardinal symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence A wind of change in AECOPD No antibiotics Increased bronchodilator Symptomatic therapy Monitoring symptoms Reevaluate Consider sputum culture Worsening clinical status or inadequate response in 72 hrs Antibiotics for AECOPD: Risk Stratification Sethi S, Murphy TF. NEJM 2008;359:2355-65.

30. New Decade New Approaches to Treat AECB “The MAESTRAL Study”

31. A prospective, multinational, multicentre, randomised, double ‑ blind, double ‑ dummy, controlled study comparing the efficacy and safety of moxifloxacin to that of amoxicillin/clavulanic acid for the treatment of subjects with acute exacerbations of chronic bronchitis (AECB) MAESTRAL (moxifloxacin in acute exacerbations trial)

32. Current questions in management of AECB Does the choice of antibiotic impact the clinical outcome of AECB? Is there adequate clinical evidence to support current guidelines for the antibiotic management of AECB? Are systemic steroids always beneficial in combination with antibiotics in the out-patient management of AECB ? 31

33. MAESTRAL STUDY DESIGN

34. Primary endpoint: clinical failure at 8 weeks post-therapy - patient’s symptoms have not improved or have worsened such that additional or alternate systemic antimicrobial and/or corticosteroid therapy is required any time up to EOT 1 Stratum 1: co-administration of systemic steroids for the current AECOPD Stratum 2: no co-administration of systemic corticosteroids for the current AECOPD Stratification 1 at enrolment per steroid use Randomisation PRIMARY ENDPOINT 8 weeks post- therapy (Day 63 ±3) 4 weeks post-therapy (Day 35 ±3) EOT (Day 13 ±1) Screening and enrolment Moxifloxacin 400 mg qd 5 days Moxifloxacin 400 mg qd 5 days Amoxicillin/clavulanic acid 875/125 mg bd 7 days Amoxicillin/clavulanic acid 875/125 mg bd 7 days MAESTRAL: a novel study vs a gold-standard therapy Wilson R et al., Int J COPD 2011;6:373–83.

35. MAESTRAL patient selection 1 Main inclusion criteria: 60 years and older Moderate-to-severe chronic bronchitis (COPD by definition) FEV 1 ≤60% at enrolment History of ≥2 AECB (treated) in past 12 months At least 20 pack-year cigarette smoking history – no fossil fuels, pollution, etc Anthonisen Type 1: exacerbation has increased sputum purulence, volume and dyspnea 2 Main exclusion criteria: Prior use of antibiotic and/or a short course of systemic corticosteroids in previous month Exacerbation in previous month 1 Wilson R et al., Int J COPD 2011;6:373–83. 2 Anthonisen NR et al., Ann Intern Med 1987;106:196–204.

36. MAESTRAL used a novel primary endpoint Wilson R et al., Int J COPD 2011;6:373–83. Primary efficacy outcome Clinical failure rates at the 8-week post-therapy visit Clinical failure defined as requirement of additional treatment for an exacerbation of respiratory symptoms (within 8 weeks post-therapy): with systemic antibiotics and/or systemic corticosteroids and/or hospitalisation with systemic antibiotics and/or systemic corticosteroids

37. MAESTRAL secondary outcomes A wind of change in AECOPD Wilson R et al., Int J COPD 2011;6:373–83. Secondary efficacy outcomes Clinical failure rates at different time points; clinical failure rates by steroid strata; for patients with positive sputum culture at enrolment, spirometry change; change in dosage/or additional respiratory concomitant medication Bacteriological outcomes Bacteriological eradication rates Questionnaires outcomes Improvement of quality of life (SGRQ); rates and speed of symptom relief (AECB-SS, a 7-item questionnaire on cough, phlegm consistency and colour, breathing difficulties, sleep disturbances and daily life disturbances) Healthcare resource utilisation/consumption outcomes Direct and indirect healthcare costs outcomes Safety outcomes Safety and tolerability

38. MAESTRAL: a global study 30 countries 150 sites Andorra, Belgium, Croatia, Czech Republic, Germany, Greece, Ireland, Italy, Latvia, Lithuania, Netherlands, Portugal, Spain, Switzerland, United Kingdom Australia Argentina, Brazil, Chile, Colombia, Peru China, Hong-Kong, Indonesia, Pakistan, Philippines, Thailand Canada, Mexico South Africa Wilson R et al., Int J COPD 2011;6:373–83. Pakistan

39. Patient disposition: optimal randomisation of a large cohort ITT with pathogens n=327 ITT with pathogens n=335 Amoxicillin/ clavulanic acid Moxifloxacin ITT/safety n=677 PP n=538 PP with pathogens n=260 Randomised n=686 ITT /safety n=675 PP n=518 PP with pathogens n=261 Randomised n=686 Wilson R et al., Int J COPD 2011;6:373–83. Enrolled n=1492 Not randomised n=120

40. Systemic corticosteroid use varied by region Received corticosteroids n/N (%) No corticosteroids n/N (%) Asia Pacific 116/417 (28)306/417 (72) Europe188/506 (37)318/506 (63) Latin America 148/362 (41)214/362 (59) South Africa 19/42 (45)23/42 (55) Canada4/25 (16)21/25 (84) ITT population Bayer Pharma AG; data on file

41. Co-medications (ITT population) Co-medicationMoxifloxacin (N=677) n (%) Amoxicillin/ clavulanic acid (N=675) n (%) Any co-medication659 (97)660 (98) Any respiratory co-medication628 (93)621 (92) Short or long-acting beta-2- agonists 1 368 (54)364 (54) Inhaled steroids389 (57)371 (55) Ipratropium or tiotropium305 (45)310 (46) Xanthine derivatives222 (33)219 (32) Bayer Pharma AG; data on file

42. MAESTRAL: CLINICAL EFFICACY

43. PopulationMoxifloxacin n/N (%) Amoxicillin/ clavulanic acid n/N (%) 95% CI 2 P value Per-Protocol 1 111/538 (20.6)114/518 (22.0)-5.89 to 3.83N/A ITT/Safety 3 138/677 (20.4)146/675 (21.6)-5.50 to 3.030.571 MAESTRAL met the primary endpoint 42 Per-protocol population

44. PopulationsMoxifloxacin n/N (%) Amoxicillin/clavulanic acid n/N (%) P value ITT with pathogens 62/327 (19.0)85/335 (25.3)0.016 PP with pathogens 50/260 (19.2)68/261 (26.1)0.030 Clinical failure (% patients) PP with pathogens P=0.030 Clinical failure (% patients) ITT with pathogens P=0.016 Moxifloxacin was superior in patients with confirmed bacterial exacerbations Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

45. Clinical failure rates 1 at 8 weeks post-therapy by systemic corticosteroid use 1 Failures and relapses are included in the failure rate calculation 95% CI stratified by region Clinical failure (% patients) With corticosteroid useWithout corticosteroid use 95% CI: –12.60, 3.7 P=0.281 95% CI: –3.65, 7.49 P=0.502 95% CI: –15.70, 2.77 P=0.168 95% CI: –4.36, 5.40 P=0.835 48/18262/18966/23676/23963/35652/32973/44170/436 Clinical failure (% patients) Wilson et al., Eur Resp J 2011; in press

46. 1 Failures and relapses are included in the failure rate calculation 95% CI stratified by region 34/126 40/119 23/94 32/93 28/201 45/216 27/166 36/168 Clinical failure (% patients) With corticosteroid use Without corticosteroid use Clinical failure rates 1 at 8 weeks post-therapy by systemic corticosteroid use 95% CI –20.8, 2.1 P=0.110 95% CI –25.8, 0.21 P=0.055 95% CI –13.6, 3.2 P=0.266 95% CI –13.9, 0.54 P=0.072 Wilson et al., Eur Resp J 2011; in press

47. MAESTRAL MICROBIOLOGICAL EFFICACY

48. Causative organisms at enrolment ( ITT with pathogens ) Most frequent pathogens by category Gram-positive Other Gram- negative Enterobacteriaceae Streptococcus pneumoniae 13% Haemophilus influenzae 21% Klebsiella pneumoniae 13% Staphylococcus aureus 6% Pseudomonas aeruginosa 17% Escherichia coli 6% Streptococcus sp. 1% Moraxella catarrhalis 12% Serratia marcescens 4% 662/1352 (49.0%) ITT patients had causative organisms isolated from sputum at baseline Sethi et al. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy. Sept 17–20, 2011, Chicago, USA. Poster L1-269.

49. OrganismMoxifloxacin mg/L Amoxicillin/clavulanic acid mg/L MedianMIC 90 RangeMedianMIC 90 Range H. influenzae (N=122)0.0150.030.002−1.01.02.01.0−4.0 P. aeruginosa (N=103)2.08.00.06−8.064.0 2.0−64.0 S. pneumoniae 1 (N=80) 0.12 0.015−2.00.031.00.015−4.0 M. catarrhalis (N=69)0.030.060.002−0.120.120.250.06−1.0 S. aureus (N=38)0.062.00.03−2.00.754.00.06−4.0 1 MIC for S. pneumoniae vs penicillin 1.0 mg/L; range 0.015−2.0 mg/L MIC changes during therapy or up to 8 weeks post-therapy were rare and were not significant in both treatment groups MIC distribution by key organism ( ITT with pathogens population ) Wilson et al., Eur Resp J 2011; in press

50. Sustained advantage for Moxifloxacin against H. influenzae Bacteriological success rates by organism and time- point Haemophilus influenzae ( ITT with pathogens population ) Wilson et al., Eur Resp J 2011; in press

51. Bacteriological eradication: initial causative pathogen absent, no new pathogen was isolated after start of study. Presumed eradication: absence of appropriate culture material for evaluation because patient has clinically improved on therapy. Persistence: initial causative pathogen still present. Presumed persistence: absence of appropriate culture material for evaluation in a patient who has not clinically improved on therapy. Continued eradication: the causative organism is absent at this time point. Continued presumed eradication: absence of appropriate culture material for evaluation because the patient has clinically improved. Bacteriological response – definitions Wilson et al., Eur Resp J 2011; in press

52. Clinical failure rates in patients with confirmed bacterial exacerbations Clinical failure (% patients) ITT with pathogensPP with pathogens P=0.030 P=0.016 Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

53. 1 Confirmed eradication vs confirmed persistence/ superinfection; 2 Clinical cure or continued clinical cure 149/194123/19886/10755/9063/8768/108 P=0.0014 P=0.003 P=0.150 Bacteriological response 1 at EOT correlated to clinical cure 2 at week 8 post-therapy ( ITT with pathogens population ) Wilson et al., Eur Resp J 2011; in press

54. 1 Includes eradication and presumed eradication 2 Indeterminates counted as non-successes Advantage seen vs H. influenzae for Avelox Eradication rates 1,2 at the end of therapy by most common organisms (ITT with pathogens population) OrganismMoxifloxacin n/N (%) Amoxicillin/clavulan ic acid n/N (%) H. influenzae 58/65 (89.2)50/75 (66.7) P. aeruginosa 31/57 (54.5)32/54 (59.3) S. pneumoniae 44/49 (89.8)33/38 (86.8) M. catarrhalis 30/36 (83.3)37/43 (86.0) S. aureus 20/23 (87.0)16/20 (80.0) Wilson et al., Eur Resp J 2011; in press

55. SAFETY

56. Event MedDRA Preferred Term (version 13.1) Moxifloxacin N=677 n (%) Amoxicillin/clavulani c acid N=675 n (%) Any adverse event (AE)220 (32.5)218 (32.3) Drug-related AE53 (7.8)41 (6.1) Serious AE (SAE)46 (6.8)51 (7.6) Serious drug-related AE4 (0.6)2 (0.3) Premature discontinuation due to drug-related AE 12 (1.8)9 (1.3) Premature discontinuation due to SAE 7 (1.0)3 (0.4) AE-related deaths3 (0.4) P>0.05 for all categories Overview of treatment-emergent adverse events through week 8 post-therapy ( ITT/safety population ) Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

57. MAESTRAL Study Results Summary – 1/2 Moxifloxacin was equivalent to amoxicillin/clavulanic acid in the treatment of acute exacerbations in outpatients with moderate-to-severe COPD. Moxifloxacin was superior to amoxicillin/clavulanic acid in terms of clinical cure at 8 weeks post-therapy for patients with confirmed bacterial exacerbations at baseline. Patients with confirmed bacterial exacerbations who received concomitant steroids generally had more severe disease and had a higher clinical failure rate than those who were not on steroids. In this sicker population of patients with confirmed bacterial exacerbations who received steroids, there was a trend for lower clinical failure rates with Moxifloxacin vs amoxicillin/clavulanic acid.

58. The overall eradication rate at end-of- therapy was higher with Moxifloxacin than with amoxicillin/clavulanic acid, mainly explained by a better efficacy against H. influenzae. There was a clear correlation between bacteriological response at end-of-therapy and clinical cure at 8 weeks post-therapy – overall and for the Moxifloxacin group. Both treatments were well-tolerated and had similar safety profiles. 57 MAESTRAL Study Results Summary – 2/2

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