Transcript Slide Set

Prevention of Viral-Induced Asthma
Montelukast in the Prevention of
Exacerbations in Children Aged 2–5 Years
with Asthma
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Burden of Asthma – One of the Most Common
Chronic Illnesses in Children
176 deaths
in US children
14 years in 1999
Affects
~5 million
children
<18 years
in the US
Number 1
chronic illness
causing
school absences
Asthma
658,000 emergency
department visits for
asthma in US children
<15 years in 1999
~3.5 million
physician or
outpatient
hospital visits
for US children
<15 years
in 1999
>8.7 million
prescriptions in the US
for children <17 years
190,000 hospitalisations
for US children <15 years in 1999
AAAAI. Pediatric Asthma: Promoting Best Practice University of Rochester 1999;
Mannino DM et al. MMWR Surveill Summ 2002;51:1–13;
American Lung Association. http://www.lungusa.org/asthma/ascpedfac99.html.
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Asthma in Pre-school Children
Weekly new cases of asthma in the UK
(per 100,000 of age group)
180
0–4 years
5–14 years
15 years
160
140
Compared with adults and
older children, pre-school
children show:
 Greatest increase in asthma
incidence
 Greatest prevalence of
wheeze
120
100
 Highest weekly
consultation rate
80
60
 Hospitalisation rate
40
– 3 times higher than older
children
20
0
76
80
84
88 92
Year
96
00
– 6 times higher than adults
National Asthma Campaign. Asthma J 2001;6(Suppl):3–14.
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Burden of Asthma on Children
• In a survey of 637 children compliant with preventer medications,
many reported inability to participate in daily activities
60
50
49%
50%
45%
40
Children
30
(%)
27%
20
10
0
Cannot
participate in
recreational
activities
Cannot do the
same things as
other children
Cannot socialise
Cannot sleep
with friends
through the night
Patient surveys, distributed by UK pharmacies, were collected from a total of 2232 respondents (534 children aged 8–14 years, 732 parents of
children aged 0–14 years, and 966 adults aged 15 years). Patients were asked what they cannot do on a bad asthma day.
The AIR Study. Asthma in Real Life. Taylor Nelson Sofres Healthcare 1997.
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Difficulties in Administering Inhaled Therapies
to Young Children (Aged 2–5 Years)

Incorrect inhaler technique

Bulky, expensive equipment

Time consuming
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Compliance Problems with Inhaled
Corticosteroids
• In a study of 24 children aged 8–12 years, actual compliance measured
by a monitoring device was much lower than thought by children
and parents
100
95%
80
58%
Compliance
60
(% prescribed
dose)
40
32%
20
0
Reported by
patient / parent
Actual compliance
Doses taken at
correct times
In a 13-week prospective study, children and parents recorded medication use in a diary, while actual medication use was monitored by the
MDI Chronolog device.
Milgrom H et al. J Allergy Clin Immunol 1996;98:1051–1057.
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Viral Infection Is a Common Cause of
Wheezing Exacerbations in Children
 In a survey, viruses were detected in up to 85% of
wheezing exacerbations, in particular:
– Rhinovirus
– Coronavirus
– Influenza virus
– Parainfluenza viruses
– Respiratory syncytial virus (RSV)
 Seasonal correlations between rates of upper
respiratory infections (URIs) and hospital
admissions for asthma
Johnston SL et al. BMJ 1995;310:1225–1229; Johnston SL et al. Am J Respir Crit Care Med 1996;154:654–660;
Pattemore PK et al. Clin Exp Allergy 1992;22:325–336.
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Inflammatory Effects of Leukotrienes in the
Airways
Increased
mucus secretion
Decreased mucus
transport
Cationic proteins
(Epithelial cell damage)
Airway
Epithelium
Increased release
of tachykinins
Eosinophil
recruitment
Blood
vessel
Sensory C
fibres
CysLTs
Smooth muscle
Oedema
Inflammatory Cells
(e.g., Mast Cells,
Eosinophils)
Contraction and
proliferation
Adapted from Hay DW. Chest 1997;111:35S–45S.
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Role of Leukotrienes in Viral-Induced
Wheezing
 In a study of 73 children, levels of leukotriene C4 (LTC4) were
>5-times higher in children with RSV-bronchiolitis than in those
with upper respiratory tract infection (URTI) without wheezing
1600
p<0.02
Mean LTC4
concentration 1200
0–7 days after
onset of
800
illness
(pg / 0.1 ml)
400
0
Bronchiolitis
(n=43)
URTI
(n=21)
Nasopharyngeal samples were taken from children aged 6 years with RSV infection hospitalised during the winters of 1986 and 1987.
Volovitz B et al. Pediatr Res 1988;24:504–507.
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In a Clinical Study, Montelukast Provided Effective
Asthma Control for Children Aged 2–5 Years
• A 12-week, double-blind study involving children with chronic asthma
Trouble
Activity
Night-time
Cough
Wheeze breathing limitation symptoms
0
10
Change
from
baseline
in
symptom
score
at week 12
(%)
20
30
40
50
23%
26%
28%
28%
31%
35%
39%
p=0.003
p=0.042
42%
42%
39%
p<0.001
p=0.007
p=0.026
60
Montelukast 4 mg (n=461)
Placebo (n=228)
A total of 689 children aged 2–5 years were randomised in a 2:1 ratio to treatment with montelukast 4 mg chewable tablet or placebo once daily.
Knorr B et al. Pediatrics 2001;108:e48.
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Prevention of Viral-Induced Asthma (PREVIA):
Primary Objective
 To determine the effect of 12 months of treatment
with montelukast, compared with placebo, on the
rate of exacerbation episodes in children aged 2–
5 years with asthma
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Asthma Exacerbation Episode
Any 3 consecutive days with:
 Daytime symptoms (average score of 4 daily
symptom questions of 1 each day), AND
 2 beta-agonist treatments each day
OR
 Inhaled corticosteroid rescue (on 3 consecutive
days) or oral corticosteroids (1 day)
OR
 Hospitalisation due to asthma
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Study Design
Period I
Period II
Placebo
Placebo
run-in
Montelukast 4 mg (or 5 mg depending on age)*
Week
-3
-2
0
8
16
24
36
48
Visits
1
2
3
4
5
6
7
8
*5 mg chewable tablet administered instead if patient turned 6 years of age during the study
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Inclusion Criteria
 Aged 2–5 years
 Pre-study
– 3 episodes of asthmatic symptoms resulting from URTI
and requiring beta agonist, lasting for 3 days within
past 12 months, with at least one of these episodes
occurring within 6 months of enrollment
– Mild asthma characterised by no symptoms or
beta-agonist use in a typical week during past 3 months
prior to enrollment
 During placebo run-in
– Symptoms (average score on 4 daily symptom
questions of 0.5) on 2 consecutive days and 4 days
in total
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Study Assessments
 Caregiver diary
– Symptoms
– Use of beta agonist
– Medical resource use for asthma
 Blood eosinophil count
 Adverse events (AEs)
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Patient Disposition
Randomised
n=549
Montelukast 4 mg
n=278
Completed
n=259
Placebo
n=271
Discontinued
n=19
Clinical AE
Lack of efficacy
Protocol deviation
Lost to follow-up
Withdrew consent
Other reason*
Completed
n=241
1
4
5
3
4
2
Discontinued
n=30
Clinical AE
Lack of efficacy
Protocol deviation
Lost to follow-up
Withdrew consent
Other reason*
10
3
5
2
7
3
*Other includes: mother lost interest in the study (did not complete diary cards) (1), patient refused to take
medication (1), unwilling to participate (2), due to frequent re-heightening (1)
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Baseline Characteristics
Montelukast 4 mg
n=278
Placebo
n=271
Total
N=549
Boys (%)
62.2
65.3
63.8
Mean age (months)
43.8
44.4
44.1
Age (%)
<36 months
36–47 months
48–59 months
60 months
30.6
33.8
23.7
11.9
25.8
35.1
25.5
13.7
28.2
34.4
24.6
12.8
Mean daytime symptom score
0.1
0.1
0.1
Mean beta-agonist puffs / 14 days
1.6
1.6
1.6
Mean eosinophil count (103/mL)
0.4
0.4
0.4
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Montelukast Significantly Reduced the Rate
of Exacerbations
p0.001
Exacerbation 3
episode
rate / year
32%
2.34
2
1.60
1
0
Montelukast 4 mg
(n=265)
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Placebo
(n=257)
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Frequency of Exacerbations
• A greater proportion of patients experienced 2 exacerbations with
montelukast compared with placebo
Patients 45
(%)
40
Montelukast 4 mg (n=265)
Placebo (n=257)
35
30
25
20
15
10
5
0
0
1
2
3
4
5
6
7
Number of Exacerbation Episodes
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>7
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Montelukast Increased the Time to First
Exacerbation
• Mean time to first exacerbation:
206 days with montelukast, 147 days with placebo
Proportion
1.0
without
exacerbation
0.8
episode
Montelukast (n=265)
Placebo (n=257)
0.6
Log-rank test p=0.024
0.4
0.2
0.0
0
2
4
6
8
10
12
Months
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Montelukast Reduced Exacerbations from
Autumn Through to Spring
Montelukast 4 mg
15
Patients
with
exacerbation
episode
(%)
10
Winter
Spring
Placebo
Summer
Autumn
5
0
JAN
FEB MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
DEC
Month (in Northern Hemisphere)
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Components of Exacerbation Episode
Patients (%)
Montelukast 4 mg
n=265
Placebo
n=257
p value
1 Exacerbation
58.1
65.4
0.087
Symptoms / beta-agonist use
17.4
30.0
0.001
Corticosteroid use
Inhaled
Oral
35.5
20.4
21.5
41.2
29.6
20.2
0.178
0.014
0.740
Hospitalisation
4.2
5.8
0.331
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Duration and Severity of Exacerbations
 In an analysis of patients who experienced
1 exacerbation, severity and duration of
exacerbation episodes were similar with
montelukast 4 mg and placebo
 Montelukast reduced frequency of exacerbations
rather than severity and duration
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Montelukast Reduced the Use of Corticosteroids
Corticosteroid
courses/
year
2.5
Montelukast 4 mg (n=265)
p=0.024
Placebo (n=257)
32%
2.0
p=0.027
1.74
40%
1.5
1.19
1.10
1.0
0.66
p=0.368
0.53
0.64
0.5
0.0
Total
Inhaled
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Oral
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Days without Asthma
Days
(%)
p=0.059
100
80
75.8%
72.7%
Montelukast 4 mg
(n=263)
Placebo
(n=256)
60
40
20
0
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Montelukast Reduced Inflammatory Cells
(Eosinophils)
p=0.01
Median
change
from
baseline*
(%)
5
3.7%
4
3
2
1
0
-1
-2
-3
-4
-5
-4.0%
Montelukast 4 mg
(n=214)
Placebo
(n=216)
*Last on-treatment value
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Summary of AEs
Patients (%)
Montelukast 4 mg
n=278
Placebo
n=271
1 AE
92.4
88.6
Drug-related AE*
5.0
4.1
Serious drug-related AE
0.4
0.4
Discontinued due to AE
0.4**
3.7
0.0
1.1
Discontinued due to drug-related AE
*Determined by investigator to be possibly, probably or definitely drug-related
**p=0.005 vs. placebo
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Drug-Related AEs Reported by 2 Patients in
Either Treatment Group
Patients (n)
Montelukast 4 mg
n=278
Placebo
n=271
Abdominal pain
3
2
Headache
1
2
Insomnia
0
2
Asthma
1
3
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PREVIA Study Summary
In children aged 2–5 years with episodic asthma
symptoms, 12 months of treatment with montelukast
 Significantly reduced the rate of exacerbations
by 32% (p0.001) and courses of inhaled
corticosteroids by 40% (p=0.027)
 Numerically reduced the rate of oral corticosteroid
courses and increased the percentage of days
without asthma
 Did not affect the average duration or severity of
exacerbations
 Was generally well tolerated
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Conclusion
 Montelukast 4 mg provides effective, convenient,
and well-tolerated asthma control for young
children aged 2–5 years with asthma
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Additional Information: Available Formulations
of Montelukast for Children
 For children aged 6 months – 2 years
– one packet of 4 mg oral granules daily
 For children aged 2–5 years
– 4 mg chewable tablet once daily, or
– one packet of 4 mg oral granules daily
 Administration of oral granules
– may be administered directly in the mouth or mixed with a
spoonful of soft food
Please refer to the full prescribing information on approved indications and dosage
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References
See notes page for reference list
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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 © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
10-05 SGA 2003-W-6675-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
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Alternative
presentation
Montelukast Reduced Exacerbations from
Autumn Through to Spring
Montelukast 4 mg
Patients
15
with
exacerbation
episode
(%)
10
Winter
Spring
Placebo
Summer
Autumn
5
0
JAN
FEB MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
DEC
Month (in Northern Hemisphere)
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