Transcript No Slide Title

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
33.0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;20:1549–1558.
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%
p0.001
–0.5
p0.001
–18.7%
p0.001
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 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
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
p0.001
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;20:1549–1558.
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
(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;20:1549–1558.
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
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;20:1549–1558.
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