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Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis One Airway, One Disease, One Approach Slide 1 One Airway, One Disease Slide 2 One Airway, One Disease Asthma and Allergic Rhinitis: Two Related Conditions Linked by One Common Airway • Frequently overlapping conditions • Involvement of similar tissues • Common inflammatory processes – Common inflammatory cells – Common inflammatory mediators Adapted from Phillip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 3 Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Have Similar Prevalence Patterns Allergic Rhinitis Asthma UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia 0 5 10 15 20 25 30 35 40 % prevalence 0 5 10 15 20 25 30 35 40 % prevalence Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms over 12 months using questionnaires. Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232. Slide 4 Epidemiologic Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Allergic Rhinitis Up to 80% of all asthmatic patients have allergic rhinitis All asthmatic patients Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32. Slide 5 Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis Is a Risk Factor for Asthma Allergic rhinitis increased the risk of asthma about threefold 12 p<0.002 10 % of patients who developed asthma 10.5 8 6 4 2 0 3.6 No allergic rhinitis at baseline (n=528) Allergic rhinitis at baseline (n=162) 23-year follow-up of first-year college students undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years Adapted from Settipane RJ et al Allergy Proc 1994;15:21–25. Slide 6 Post Hoc Resource Use Analysis of IMPACT Allergic Rhinitis Increased the Risk of Asthma Attacks 25 p=0.046 20 % of patients 15 21.3 17.1 10 0 Patients with asthma (n=597) Patients with asthma + allergic rhinitis (n=893) Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks Adapted from Bousquet J et al Clin Exp Allergy 2005;35:723–727. Slide 7 Allergic Rhinitis Worsens Asthma Allergic Rhinitis Doubled the Risk of ER Visits in Patients with Asthma 4.0 p=0.029 3.5 3.6 3.0 % of patients 2.5 2.0 1.5 1.7 1.0 0.5 0 Patients with asthma (n=597) Patients with asthma + allergic rhinitis (n=893) Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks ER=emergency room Adapted from Bousquet J et al Clin Exp Allergy 2005;35:723–727. Slide 8 Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Odds of Hospitalization for Asthma by 50% p<0.006 0.8 0.7 0.76 0.6 % of 0.5 patients hospitalized 0.4 annually 0.3 0.45 0.2 0.1 0 Patients with asthma (n=22,692) Patients with asthma + allergic rhinitis (n=4611) Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in general practice in the UK Adapted from Price D et al Clin Exp Allergy 2005;35:282–287. Slide 9 Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Number of Prescriptions for Rescue Therapy (SABA) in Patients with Asthma 3.3 3.2 3.1 3.0 Annual 2.9 prescriptions 2.8 per patient 2.7 2.6 2.5 2.4 0 p<0.0001 3.2 2.7 Patients with asthma (n=22,692) Patients with asthma + allergic rhinitis (n=4611) Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in general practice in the UK SABA=short-acting beta2-agonists Adapted from Price D et al Clin Exp Allergy 2005;35:282–287. Slide 10 One Airway, One Disease Both Asthma and Allergic Rhinitis Are Inflammatory Conditions • Asthma is fundamentally a disease of inflammation – Inflammation of the lower airways causes bronchoconstriction and airway hyperresponsiveness, resulting in asthma symptoms • Allergic rhinitis is an IgE-mediated inflammatory disorder – Inflammation of the nasal membranes in response to allergen exposure results in nasal symptoms IgE=immunoglobulin E Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149. Slide 11 One Airway, One Disease Allergic Rhinitis and Asthma Have Common Triggers • Outdoor allergens – Pollens – Molds • Indoor allergens – House-dust mites – Animal dander – Insects (e.g., cockroach allergen) • NSAIDs (e.g., aspirin) NSAIDs=nonsteroidal anti-inflammatory drugs Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses, 2001. Slide 12 One Airway, One Disease Allergic Rhinitis and Asthma Share Common Inflammatory Cells and Mediators Membrane-bound IgE Mast cell Preformed Mediators Cysteinyl leukotrienes Prostaglandins Platelet-activating factor Early-phase response Allergen Eosinophils T cells Cytokines Inflammatory mediators Late-phase response Adapted from Casale TB et al Clin Rev Allergy Immunol 2001;21:27–49; Kay AB N Engl J Med 2001;344:30–37. Slide 13 Shared Pathophysiology of Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Share a Similar Inflammatory Process and Occur in the Mucosa Allergic rhinitis Asthma Bronchial mucosa Nasal mucosa Eosinophil infiltration Eos=eosinophils; neut=neutrophils; MC=mast cells; Ly=lymphocytes; MP=macrophages Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149. Slide 14 One Airway, One Disease Symptoms Correlate with the Early- and Late-Phase Responses in Allergic Rhinitis and Asthma Upper Airways (Allergic rhinitis) Score for nasal symptoms Sneezing Nasal pruritus Congestion Rhinorrhea Antigen challenge Lower Airways (Asthma) Late phase Immediate (early) phase 1 3–4 8–12 24 Time post-challenge (hours) 100 FEV1 (% change) 50 0 0 1 2 3 4 5 6 7 8 9 10 24 Time (hours) FEV1=forced expiratory volume in one second Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604. Slide 15 Clinical Links between Allergic Rhinitis and Asthma Patients with Allergic Rhinitis Experience Increased Bronchial Hyperresponsiveness Prevalence of bronchial hyperresponsiveness* 60 (n=27) p<0.02 50 48 40 % of patients 30 20 10 0 11 Out of season In season Study of bronchial hyperreactivity in patients (mean age 20 years) with hay fever; challenges were performed in the fall of one year and approximately six months later. *PD20 <1 mg after carbachol challenge PD=provocation dose Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358–363. Slide 16 Clinical Links between Allergic Rhinitis and Asthma Allergen Challenge to the Nose Increases Bronchial Hyperresponsiveness Change from baseline in PC20* 3 Geometric mean PC20 (methacholine, mg/ml) Placebo (n=5) Allergen (n=5) p=0.0009 p=0.011 2 0 Baseline 0.5 hour post-challenge 4.5 hours post-challenge Randomized, crossover two-day investigation of the relationship between allergic rhinitis and lower airway dysfunction in patients with allergic rhinitis and asthma (mean age 31.4 years) PC=post-challenge *Lower PC20 values indicate greater hyperresponsiveness Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611–618. Slide 17 Clinical Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Nasal Inflammation Eosinophil counts in the nasal mucosa 18 (n=9) (n=8) (n=10) 16 14 12 Eosinophils/ field of nasal biopsy 10 8 6 4 2 p<0.001 p<0.001 0 Rhinitis No rhinitis Control Asthmatic Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in non-atopic subjects 20 to 66 years of age Bars represent median values. Adapted from Gaga M et al Clin Exp Allergy 2000;30:663–669. Slide 18 Clinical Links between Allergic Rhinitis and Asthma Inflammatory Changes in the Nasal and Bronchial Mucosa Are Correlated 40 (n=17) 35 30 Asthmatic nasal mucosa eosinophils 25 20 15 10 5 r=0.851, p<0.001 0 0 5 10 15 20 25 30 Asthmatic bronchial mucosa eosinophils Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669. Slide 19 Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases a Marker of Inflammation (Eosinophils) in Nasal and Bronchial Tissues Nasal tissue (lamina propria) 100 Bronchial tissue (subepithelial layer) Eosinophils 80 (number cells/ 60 mm2) d 1200 c 800 40 400 20 0 b 1600 a a 0 T0 T24 Control patients (n=8) Allergic patients (n=8) T0 Unchallenged Allergenleft lung challenged right middle lobe T24 Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years) T0= before challenge; T24=24 hours post-challenge ap<0.05; bp<0.01; cp=0.001; dp=0.002 Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057. Slide 20 Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases Systemic Markers of Inflammation * 600 ** 500 Peripheral blood eosinophils (106 cells/L) Control patients (n=8) Allergic patients (n=8) 400 300 200 100 0 T0 T24 Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years) T0= before challenge; T24=24 hours post-challenge *p<0.05; **p<0.01 Data presented as median ± range Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057. Slide 21 Shared Pathophysiology of Allergic Rhinitis and Asthma Summary • Allergic rhinitis and asthma share several pathophysiologic characteristics – Common triggers – Similar inflammatory cascade on exposure to allergen – Cysteinyl leukotrienes are common mediators in upper and lower airway diseases – Similar pattern of early- and late-phase responses – Infiltration by the same inflammatory cells (e.g., eosinophils) – Several potential connecting pathways, including systemic transmission of inflammatory mediators Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Kay AB N Engl J Med 2001;344:30–37; Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford, UK: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Togias A Allergy 1999;54(suppl 57): 94–105. Slide 22 One Airway, One Disease ARIA and IPAG Guidelines Recommend a Combined Approach to Managing Asthma and Allergic Rhinitis • Patients with allergic rhinitis should be evaluated for asthma • Patients with asthma should be evaluated for allergic rhinitis • A strategy should combine the treatment of upper and lower airways in terms of efficacy and tolerability ARIA=Allergic Rhinitis and its Impact on Asthma; IPAG=International Primary Care Airways Groups Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; International Primary Care Airways Group, Los Angeles, California, USA, MCR Vision, 2005. Slide 23 Cysteinyl Leukotrienes—Important Mediators of Both Asthma and Allergic Rhinitis Slide 24 Cysteinyl Leukotrienes in Asthma: Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation Cysteinyl leukotrienes Montelukast Blocks cysteinyl leukotrienes Steroid-sensitive mediators (e.g., cytokines) Inhaled steroids Inhibit steroidsensitive mediators (e.g., cytokines) The slide represents an artistic rendition. Adapted from Diamant Z, Sampson AP Clin Exp Allergy 1999;29:1449–1453; Barnes PJ Am J Respir Crit Care Med 1996;154:S21–S27; Claesson H-E, Dahlén S-E J Intern Med 1999;245:205–227; Price DB et al Thorax 2003;58:211–216. Slide 25 Cysteinyl Leukotrienes—Mediators of Asthma Inhaled Corticosteroids Do Not Affect Sputum Leukotriene Levels in Patients with Asthma 14 13* 12 10 Sputum cysteinyl leukotriene 8 levels 6 (ng/ml) 11.4** 9.4* 6.4 4 2 0 Controls (n=10) All patients with asthma (n=26) Patients with persistent asthma Patients with acute attacks (n=12) (n=10) Study of the use of induced sputum to assess airway eicosanoid production in 10 healthy and 26 asthmatic adults (mean age 40 to 57 years in each treatment group) *p<0.02 vs. normal individuals; **p<0.05 vs. normal individuals Adapted from Pavord ID et al Am J Respir Crit Care Med 1999;160:1905–1909. Slide 26 Cysteinyl Leukotrienes—Mediators of Asthma Cysteinyl Leukotrienes Are Important Mediators of Nasal Obstruction 150 % change in NAR 125 * 100 Challenge (n=7) 1/2 1 3 5 7 9 11 Hour • LTD4 was approximately 5000 times more potent than histamine in mediating nasal responses Study to examine the clinical significance of LTD4 vs. antigen and histamine in adult patients (mean age 25.0–26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen. *p<0.05 vs. baseline NAR=nasal airway resistance Adapted from Okuda M et al Ann Allergy 1988;60:537–540. Slide 27 Cysteinyl Leukotrienes—Mediators of Both Asthma and Allergic Rhinitis Cysteinyl Leukotriene Challenge Increases Rhinorrhea in Allergic Rhinitis 1.00 (n=8) 0.75 Nasal secretion (10-2 g/min) 0.50 0.25 0 0 ~5 ~10 ~15 ~20 Time (minutes) Study to examine the clinical significance of LTD4 vs. antigen and histamine in adult patients (mean age 25.0–26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen. Adapted from Okuda M et al Ann Allergy 1988;60:537–540. Slide 28 Cysteinyl Leukotrienes—Mediators of Asthma Role of Cysteinyl Leukotrienes in Earlyand Late-Phase Allergic Response Early phase Late phase Histamine, cysteinyl leukotrienes, prostaglandins, thromboxanes, heparin, proteases, PAF (predominant) Score for nasal symptoms Cysteinyl leukotrienes, cytokines (predominant) Cysteinyl leukotrienes Sneezing Nasal pruritus Congestion Rhinorrhea Antigen challenge 1 3–4 8–12 24 Time post-challenge (hours) PAF=platelet-activating factor Adapted from Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Rachelevsky G J Pediatr 1997;131:348–355; Rouadi P, Naclerio R. SRS-A to Leukotrienes: The Dawning of a New Treatment. S Holgate, S Dahlen, eds. Oxford, England: Blackwell Science, 1997; Creticos PS et al N Engl J Med 1984;31:1626–1630. Slide 29 Cysteinyl Leukotrienes—Mediators of Asthma Correlation of Cysteinyl Leukotriene Release with Symptoms in Allergic Rhinitis Predominant mediator types Most commonly associated allergy symptoms Early-phase allergic response (within minutes) Cysteinyl leukotrienes Histamine Sneezing Nasal itching Rhinorrhea Nasal obstruction Late-phase allergic response (within 4+ hours) Cysteinyl leukotrienes Cytokines Prolonged nasal obstruction Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32; Vignola AM et al Allergy 1998;53:833–839; Meltzer EO Ann Allergy Asthma Immunol 2000;84:176–185; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Settipane GA Arch Intern Med 1981;141:328–332; Magnan A et al Eur Respir J 1998;12:1073–1078; Yssel H et al Clin Exp Allergy 1998;5:104–109, discussion 17–18. Slide 30 Efficacy of Montelukast in Asthma Patients with Seasonal Allergic Rhinitis Slide 31 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Study Design and Objective Period I Single-blind run-in Period II Double-blind treatment Montelukast* (n=415) Placebo Placebo (n=416) –3 to 5 days 0 2 weeks • To evaluate the efficacy of montelukast in improving the symptoms of allergic rhinitis in patients with active asthma and active allergic rhinitis during the allergy season *10 mg once daily at bedtime Short-acting beta2-agonists were used as needed in both groups. Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 32 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Inclusion Criteria: Active Asthma and Daily Rhinitis Symptoms Asthma • 1-year history (dyspnea, wheezing, chest tightness, cough) • 1 of 4 criteria for active asthma – – – – Asthma symptoms once weekly Reversible airway obstruction History of methacholine hyperresponsiveness 1-year history of exercise-induced bronchoconstriction • Stable dose of inhaled corticosteroid and/or long-acting beta2-agonist use Allergic Rhinitis • 2-year clinical history (rhinitis symptoms worsening during allergy season) • Daily rhinitis symptoms at least mild to moderate during placebo run-in • Positive skin test to 3 allergens active during study season Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 33 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Endpoints Composite Daily Rhinitis Symptom Score Daytime nasal symptoms • Congestion • Rhinorrhea • Pruritus • Sneezing Nighttime symptoms • Difficulty falling asleep • Nighttime awakenings • Nasal congestion on awakening (0–3 scale, mild to severe) Secondary/other endpoints • Rhinoconjunctivitis quality of life • Patients’ and physicians’ global evaluations of allergic rhinitis • Patients’ and physicians’ global evaluations of asthma • As-needed beta2-agonist use Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 34 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Baseline Characteristics of Patients Montelukast (n=415) Placebo (n=416) Age (year) Mean±SD Range 33.013.2 15–78 33.613.7 15–80 Gender (% of patients) Male Female Duration of allergic rhinitis (years) Duration of asthma (years) Inhaled corticosteroid therapy at baseline (% of patients) Asthma symptoms once weekly (% of patients) Asthma symptoms twice weekly (% of patients) 36% 64% 19.611.9 17.512.2 38% 90% 57% 35% 65% 19.012.2 16.511.9 43% 93% 62.5% Season studied (% of patients) Spring Fall FEV1 (% predicted) Daily rhinitis symptoms score 84% 16% 84% 1.750.42 85% 15% 84% 1.770.42 Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 35 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Significantly Reduced Daily Rhinitis Symptoms Scores* 0 Daily rhinitis symptoms Daytime nasal symptoms Nighttime symptoms –0.1 Change –0.2 from baseline –0.3 (mean) –0.4 –11.8% –11% –18.2% –10.5% –18% p0.001 –0.5 p0.001 –18.7% p0.001 Placebo (n=416) Montelukast (n=415) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15 to 85 years of age with allergic rhinitis during the allergy season *Scored on a 4-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 36 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Reduced Daily Rhinitis Symptoms Regardless of Asthma Status at Study Start Effect Greater 0 Treatment difference: montelukast minus placebo (LS meanSE) –0.1 –0.2 Yes No n=335 n=490 twice <twice weekly weekly <80% 80% 12% <12% n=495 n=316 n=503 n=427 n=392 –0.3 On inhaled corticosteroids n=330 Asthma symptoms FEV1 % predicted Beta2-agonist reversibility Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season LS=least-squares Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 37 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Global Evaluations of Clinical Status and Quality of Life Global evaluations of allergic rhinitis* 5 p0.001 p0.001 Placebo (n=416) Montelukast (n=415) 4 Treatment score (mean±SD) 3 2.77 2 2.39 2.76 2.41 1 0 Patients Physicians • Montelukast significantly improved rhinoconjunctivitis quality-of-life scores versus placebo (p<0.01) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season *Scored on a 6-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 38 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Asthma Control Global evaluations of asthma* 2.8 Placebo (n=416) Montelukast (n=415) 2.6 Treatment score 2.4 (mean) p<0.01 p<0.05 2.52 2.52 2.34 2.28 2.2 0 Patients Physicians • Montelukast significantly reduced beta2-agonist use (p0.005 vs. placebo) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season *Scored on a 6-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 39 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Conclusions In asthmatic patients with concomitant seasonal allergic rhinitis, montelukast demonstrated significant improvements in • Allergic Rhinitis – Daily rhinitis symptoms score (average of the daytime nasal symptoms score and the nighttime symptoms score)a – Rhinoconjunctivitis quality of lifeb – Global evaluations of allergic rhinitis by patient and by physiciana • Asthma – Global evaluations of asthma by patientb and by physicianc – Beta2-agonist used ap0.001 vs. placebo; bp<0.01 vs. placebo; cp<0.05 vs. placebo; dp0.005 vs. placebo Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. Slide 40 Efficacy of Montelukast in Asthma Patients with Concomitant Allergic Rhinitis— COMPACT Subanalysis Slide 41 Objective of COMPACT Study and Subanalysis • To determine whether adding montelukast 10 mg to budesonide (800 µg) would provide greater benefits than doubling the dose of budesonide (to 1600 µg) in – Adult patients with asthma (OVERALL COMPACT study) – Adult patients with asthma and allergic rhinitis (SUBANALYSIS) COMPACT=Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy Adapted from Price DB et al Thorax 2003;58:211–216; Price DB et al Allergy 2006; in press. Slide 42 COMPACT Study Study Design Montelukast 10 mg once daily + Budesonide 400 µg twice daily Budesonide 400 µg twice daily (n=448) Budesonide 800 µg twice daily + Oral placebo montelukast (n=441) 0 1 4 8 12 16 Weeks Period I Run-in (4 weeks) Single-blind Period II Active treatment (12 weeks) Double-blind Adapted from Price DB et al Thorax 2003;58:211–216. Slide 43 COMPACT Study Inclusion Criteria • Age 15 to 75 years • Asthma of at least one year’s duration • Asthma not optimally controlled (judged by investigator) • Regular inhaled corticosteroid use* • Baseline FEV1 ≥50% of predicted at visits 1 and 3 • Beta2-agonist reversibility ≥12% in FEV1 • Beta2-agonist use ≥1 puff/day during the last two weeks of run-in period *Dose range: 600–1200 µg/day of budesonide, beclomethasone, triamcinolone, flunisolide, or 300–800 µg/day of fluticasone Adapted from Price DB et al Thorax 2003;58:211–216. Slide 44 COMPACT Study Montelukast + Budesonide Improved Morning PEF Progressively over 12 Weeks 440 Montelukast 10 mg + budesonide 800 µg (n=448) Budesonide 1600 µg (n=441) 430 420 Morning PEF* (L/min) 410 400 390 380 –14 –7 0 7 14 21 28 35 42 56 63 70 77 84 Days after randomization PEF=peak expiratory flow rate *Mean measurement before administration of study medication Adapted from Price DB et al Thorax 2003;58:211–216. Slide 45 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Definition of Groups in Analysis • Asthma+AR Patients with asthma and allergic rhinitis, defined by both positive patient history and confirmed physician diagnosis • Asthma–AR Patients with asthma but without both a patient history and physician diagnosis of allergic rhinitis Adapted from Price DB et al Allergy 2006; in press. Slide 46 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Statistical Analysis • Analysis of covariance (ANCOVA) model used to test each endpoint – Treatment and study site used as factors – Appropriate baseline values used as covariate Adapted from Price DB et al Allergy 2006; in press. Slide 47 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Baseline Characteristics of Patients Asthma + allergic rhinitis (n=410) Asthma (n=479) Age (year, median) Gender (% of patients) Male Female Race (% of patients) White Black Asian Other 43 45 42 58 38 62 78 1 6 15 76 <1 4 19 FEV1 (% of predicted, mean) 69 67 History of atopic dermatitis (% of patients) 19 12 Adapted from Price DB et al Allergy 2006; in press. Slide 48 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Montelukast Provided Greater Improvements in Morning PEFR than Budesonide Asthma + Allergic Rhinitis Patients 50 Montelukast (n=216)* Budesonide (n=184)** 40 LS mean ±SE change from baseline (L/min) 30 20 p=0.028 10 0 0 4 8 12 Weeks • The primary endpoint of the COMPACT study was morning PEF LS=least squares *Montelukast 10 mg once daily + budesonide 400 µg twice daily; **Budesonide 800 µg twice daily Adapted from Price DB et al Allergy 2006; in press. Slide 49 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Montelukast Provided Greater Improvements in Morning PEFR than Budesonide in Patients Who Received Rhinitis Medications* Asthma + Allergic Rhinitis Patients 60 40 p=0.017 LS mean ±SE change from baseline (L/min) 20 0 Montelukast (n=33)** Budesonide (n=23)*** –20 0 4 8 12 Weeks *Intranasal steroids, antihistamines, or other treatments for rhinitis; **Montelukast 10 mg once daily along with budesonide 400 µg twice daily; ***Budesonide 800 µg twice daily Adapted from Price DB et al Allergy 2006; in press. Slide 50 Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Conclusion In the subgroup of asthma patients from the COMPACT study who had concomitant allergic rhinitis • The addition of montelukast to budesonide provided significantly greater improvements in lung function than doubling the dose of budesonide (p<0.05) Adapted from Price DB et al Allergy 2006; in press. Slide 51 Efficacy of Montelukast in Asthma Patients with Seasonal Aeroallergen Sensitivity Slide 52 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Study Design and Objective • To assess the treatment effect of montelukast 10 mg vs. placebo on daytime asthma symptoms as measured by daily diaries during a threeweek treatment period Montelukast (n=225)* Placebo Placebo (n=230) Day –14 Day –4 Washout Week 0 Period I Placebo run-in Week 3 Period II Double-blind *10 mg once daily in the evening Albuterol was used as needed in both groups. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 53 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Inclusion Criteria • ≥18 years of age • Clinical history of chronic asthma (≥1 year) active during allergy season • Predetermined level of asthma symptoms (32 points per week on 0–6 point daily scale) • Baseline FEV1 ≥60% predicted • Airway reversibility (FEV1 increase ≥12% after beta2-agonist use) • Positive skin-prick test reaction to at least two geographically relevant seasonal aeroallergens • Nonsmokers for ≥1 year; smoking history of ≤10 pack-years Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 54 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Endpoints • Primary – Daytime asthma symptoms • Secondary – Nighttime symptoms – AM and PM peak expiratory flow rate (PEFR) – Beta2-agonist use • Exploratory – Global assessments of change in allergic rhinitis symptoms over the study course Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 55 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Baseline Characteristics of Patients Variable Age, year: mean (range) Gender (% female) Race (%) White Black Hispanic Other History of allergic rhinitis (%) FEV1 (% predicted)* Beta2-agonist reversibility (%)* Daytime symptom score (0–6 scale)* Nighttime symptom score (0–3 scale)* Beta2-agonist use (puffs/day)* AM peak expiratory flow rate (L/min)* PM peak expiratory flow rate (L/min)* Montelukast (n=225) Placebo (n=230) 35.5 (18–66) 72.4 36.8 (18–76) 67.8 80.0 11.6 6.2 2.2 99.6 83.3 (12.3) 19.8 (9.2) 2.6 (0.8) 0.6 (0.5) 3.1 (1.8) 366.7 (93.8) 370.5 (93.9) 82.6 9.1 5.7 2.6 99.1 82.2 (13.6) 20.7 (11.2) 2.6 (0.8) 0.6 (0.5) 3.0 (1.9) 367.0 (94.8) 374.1 (92.8) *Mean (SD) Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 56 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Daytime Asthma Symptom Scores (Primary Endpoint) 0.1 Montelukast (n=223) Placebo (n=229) 0 –0.1 Change –0.2 from baseline (LS mean±SE) –0.3 –0.34 –0.4 –0.5 –0.54 –0.6 –0.7 p=0.002 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 57 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Asthma Control Change from baseline (mean)b 0 –0.1 –0.2 –0.3 –0.4 –0.5 –0.6 –0.7 –0.8 –0.9 Beta2-agonist use (puffs/day)a 0 –0.05 –0.4% Nighttime symptom scorea –0.07% (–0.12 to –0.02) (–0.6 to –0.2) –0.10 –0.17% –0.15 –0.8% (–0.22 to –0.12) (–1.0 to –0.6) –0.20 p=0.003c Placebo (n=416) p<0.001c Montelukast (n=415) aA negative change from baseline indicates a favorable outcome for this endpoint. mean change (95% confidence interval [CI]) from baseline and treatment differences (95% CI) from ANOVA model with effects for treatment, center, and baseline value. cNo adjustment for multiple tests was made. bAdjusted Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 58 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Lung Function PEFR (L/min)a AM 20 (L/min)a p<0.001c 15 Change from baseline (mean)b PM PEFR 17.2% (11.3 to 23.1) p<0.001c 10 11.3% (5.5 to 17.1) 5 1.3% (–4.4 to 7.0) 0 –2.0% –5 (–7.7 to 3.6) Placebo (n=416) Montelukast (n=415) aA positive change from baseline indicates a favorable outcome for this endpoint. mean change (95% CI) from baseline and treatment differences (95% CI) from ANOVA model with effects for treatment, center, and baseline value. cNo adjustment for multiple tests was made. bAdjusted Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 59 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Global Evaluations of Allergic Rhinitis 6.0 5.0 4.0 Score* (LS mean±SE) 3.0 2.0 p=0.054 2.15 2.40 Montelukast (n=205) Placebo (n=218) 1.0 0 *Seven-point scale in which higher scores indicate more deterioration in symptoms since the start of the study. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 60 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Tolerability Profile • Montelukast comparable to placebo in proportion of patients with clinical and laboratory adverse events • Similar incidence of discontinuations due to non– drug-related clinical adverse events – 2.2% (5 patients) with montelukast – 3.0% (7 patients) with placebo Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 61 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Conclusions • In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast 10 mg provided significant improvement in asthma control when compared to placebo Daytime symptom score Beta2-agonist use Nighttime asthma symptom score AM and PM PEFR Global asthma evaluations • Montelukast 10 mg was well tolerated Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Slide 62 Montelukast in Asthma Patients with Concomitant Allergic Rhinitis Summary • Allergic rhinitis and asthma are inflammatory disorders that have • • • • been linked epidemiologically, pathophysiologically, and clinically as “one airway disease” Allergic rhinitis increases morbidity, therapeutic needs, and use of health-care resources in patients with asthma ARIA and IPAG recommend a combined strategy for the management of coexistent allergic rhinitis and asthma when possible Cysteinyl leukotrienes are mediators of both allergic rhinitis and asthma The cysteinyl leukotriene modifier montelukast has been shown to improve lung function, symptoms, and quality of life in asthma patients with concomitant seasonal allergic rhinitis Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Philip G et al Curr Med Res Opin 2004;20: 1549–1558; Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada; International Primary Care Airways Group, Los Angeles, California, USA, MCR Vision, 2005. Slide 63 References Please see notes page. Slide 64 References (continued) Please see notes page. Slide 65 References (continued) Please see notes page. Slide 66 Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis One Airway, One Disease, One Approach Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 3-07 SGA 2006-W-286990-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com Slide 67