Transcript No Slide Title

Efficacy of Montelukast
in Asthma Patients
with Allergic Rhinitis
One Airway, One Disease, One Approach
Slide 1
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One Airway, One Disease
Slide 2
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One Airway, One Disease
Asthma and Allergic Rhinitis: Two Related
Conditions Linked by One Common Airway
• Frequently overlapping conditions
• Involvement of the same tissues
• Common inflammatory processes
– Common inflammatory cells
– Common inflammatory
mediators
Adapted from Phillip G et al Curr Med Res Opin 2004;20(10):1549–1558.
Slide 3
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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
0
5
10 15 20 25 30 35 40
% prevalence
% 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.
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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.
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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.
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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. Poster presented at the European Academy of Allergology and Clinical Immunology (EAACI), June 12–16,
2004, Amsterdam. Poster 141.
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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
2.5
% of
patients
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. Poster presented at the European Academy of Allergology and Clinical Immunology (EAACI), June 12–16,
2004, Amsterdam. Poster 141.
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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 a general
practice in the UK
Adapted from Price D et al Clin Exp Allergy 2005, in press.
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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 a general practice
in the UK
SABA=short-acting beta2-agonists
Adapted from Price D et al Clin Exp Allergy 2005, in press.
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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.
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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)
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
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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(1):27–49; Kay AB N Engl J Med 2001;344:30–37.
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Shared Pathophysiology of Allergic Rhinitis and Asthma
Allergic Rhinitis and Asthma Share a Common
Inflammatory Process and Occur in the Same
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.
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One Airway, One Disease
Symptoms Correlate with the Early- and Late-Phase
Responses in Allergic Rhinitis and Asthma
Upper
Airways
(Allergic
rhinitis)
Sneezing
Nasal pruritus
Congestion
Rhinorrhea
Antigen
challenge
Lower
Airways
(Asthma)
Late phase
Immediate (early) phase
Score for nasal
symptoms
1
3–4
8–12
24
Time postchallenge (hours)
100
FEV1
(% change)
50
0
0
1
2
3
4
5
6
7
8
9
10
24
Time (hours)
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.
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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.
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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 hr
4.5 hr
postchallenge postchallenge
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=postchallenge
*Lower PC20 values indicate greater hyperresponsiveness
Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611–618.
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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 atopic
subjects 20 to 66 years of age
Bars represent median values.
Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669.
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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.
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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 postchallenge; 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.
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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 postchallenge; *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.
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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(1):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.
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One Airway, One Disease
ARIA 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
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334.
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Cysteinyl Leukotrienes—Important Mediators
of Both Asthma and Allergic Rhinitis
Slide 24
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Cysteinyl Leukotrienes in Asthma: Dual Pathways of Inflammation
Montelukast Combined with a Steroid
Affects the Dual Pathways of Inflammation
Steroid-sensitive
mediators
(e.g., cytokines)
Cysteinyl
leukotrienes
Montelukast
Inhaled steroids
Inhibits cysteinyl
leukotrienes
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.
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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.
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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 versus 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.
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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 versus 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 LTD 4, histamine,
or antigen.
Adapted from Okuda M et al Ann Allergy 1988;60:537–540.
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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
Score for
nasal
symptoms
Cysteinyl leukotrienes,
cytokines (predominant)
Cysteinyl leukotrienes
Sneezing
Nasal pruritus
Congestion
Rhinorrhea
Antigen challenge
1
3–4
8–12
24
Time postchallenge (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
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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(10):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(2):176–185; Casale TB, Amin BV Clin Rev Allergy
Immunol 2001;21(1):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.
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Efficacy of Montelukast in Asthma
Patients with Seasonal Allergic Rhinitis
Slide 31
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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(10):1549–1558.
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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(10):1549–1558.
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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(10):1549–1558.
Slide 34
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Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis
Baseline Characteristics of Patients
Montelukast
(n=415)
Placebo
(n=416)
Age (years)
Mean±SD
Range
33.013.2
15–78
33.613.7
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%
19.611.9
17.512.2
38%
90%
57%
35%
65%
19.012.2
16.511.9
43%
93%
62.5%
Season studied (% of patients)
Spring
Fall
FEV1 (% predicted)
Daily rhinitis symptoms score
84%
16%
84%
1.750.42
85%
15%
84%
1.770.42
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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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%
p0.001
p0.001
–18.7%
p0.001
–0.5
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(10):1549–1558.
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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 meanSE)
–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
Beta-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
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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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*
p0.001
5
p0.001
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(10):1549–1558.
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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
2.2
2.28
0
Patients
Physicians
• Montelukast significantly reduced beta2-agonist use
(p0.005 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(10):1549–1558.
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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
ap0.001
vs. placebo; bp<0.01 vs. placebo; cp<0.05 vs. placebo; dp0.005 vs. placebo
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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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 study)
– Patients with asthma and allergic rhinitis
(SUBGROUP analysis)
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. Presentation at the World Allergy Organization Biannual Meeting,
September 2003, Vancouver, British Columbia, Canada.
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COMPACT Study Design
Period I
Run-in (4 weeks)
Single-blind
Period II
Active treatment (12 weeks)
Double-blind
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
Adapted from Price DB et al Thorax 2003;58:211–216.
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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
*Mean measurement before administration of study medication
Adapted from Price DB et al Thorax 2003;58:211–216.
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Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT
Statistical Analysis
• All patients with a baseline and at least one
on-treatment value were included in this intention-totreat analysis
• Treatment comparisons were based on an analysis
of covariance (ANCOVA) model, with corresponding
baseline value included as a covariate and the
treatment group as a factor
• All analyses of patient subgroups were post hoc
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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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. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT
Baseline Characteristics of Patients
Asthma +
Allergic Rhinitis
(n=410)
Asthma
(n=479)
43
15–74
45
15–75
42
58
15
38
62
13
381
360
History of exercise-induced asthma
(% of patients)
83
80
Skin tested for allergies (% of patients)
74
58
History of atopic dermatitis (% of patients)
19
12
Age (years)
Median
Range
Gender (% of patients)
Male
Female
Duration of asthma (years)
Median morning PEF (L/min)
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT
Montelukast Provided Greater Improvements
in Morning PEF in Asthma Patients with
Concomitant Allergic Rhinitis
Montelukast (n=433)*
Budesonide (n=425)**
50
Change
from
baseline
(L/min, LS
meanSEM)
Montelukast (n=216)*
Budesonide (n=184)**
50
40
40
30
30
p=0.36
20
20
10
10
0
0
0
4
8
12
p<0.03
0
4
Weeks
8
12
Weeks
*Montelukast 10 mg once daily + budesonide 400 µg twice daily; **Budesonide 800 µg twice daily
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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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 greater
improvements in reducing airway obstruction than
doubling the dose of budesonide
– Improvements in morning PEF were similar in both
treatment groups (primary endpoint)
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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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 recommends 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(1):27–49; Philip G et al Curr Med Res 2004;20(10):
1549–1558; Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia,
Canada.
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References
Please see notes page.
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References (continued)
Please see notes page.
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References (continued)
Please see notes page.
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References (continued)
Please see notes page.
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Efficacy of Montelukast in Asthma
Patients with Allergic Rhinitis
Before prescribing, please consult
the manufacturers’ prescribing information.
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
1-06 SGA 2004-W-6776-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
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