Transcript No Slide Title

Investigation of Montelukast
as a Partner Agent
for Complementary Therapy
Asthma Is an Inflammatory Disease
of the Airways
GINA Guidelines Recommendations:
• Regular use of anti-inflammatory medication
• Initial therapy with low-dose inhaled corticosteroids
for mild persistent asthma
• Additional therapy for patients with asthma who
continue to experience symptoms despite taking
inhaled corticosteroids, such as:
– Long-acting beta agonists (LABA)
– Leukotriene receptor antagonists (LTRA)
Adapted from Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention. NHLBI/WHO
Workshop Report, National Institutes of Health Publication No. 02-3659, Bethesda, MD, 2002; Global Initiative for Asthma
(GINA): Pocket Guide for Asthma Management and Prevention, National Institutes of Health Publication No. 95-3659B,
Bethesda, MD, 1998.
Long-Acting Beta Agonists as a Second
Therapeutic Agent
Advantages
Concerns
• In clinical studies,
increased effectiveness
vs. increasing the
corticosteroid dose in
improving:
• In two clinical studies,
development of tolerance to
bronchoprotective effects
with chronic exposure that
does not appear to be
overcome by corticosteroids
– asthma symptoms
– lung function
• Potential risk of masking
underlying airway
inflammation and worsening
asthma
Adapted from Greening AP et al Lancet 1994;344:219-224; Woolcock A et al Am J Respir Crit Care Med 1996;153:1481-1488;
Murray JJ et al Allergy Asthma Proc 1999;20(3):173-180; Yates DH et al Am J Respir Crit Care Med 1996;154:1603-1607;
Kalra S et al Chest 1996;109(4):953-956; McIvor RA et al Am J Respir Crit Care Med 1998;158:924-930.
Potential Masking Effects of Salmeterol on
Airway Inflammation in a Steroid Tapering Study
Mean (SD) sputum eosinophil count one week before exacerbation*
p=0.006
Eosinophils
(% of total
sputum
leukocytes)
25
20
19.9 (17.6)
15
9.3 (29.8)
10
5
0
Salmeterol
50 µg twice daily
(n=13)
Placebo
(n=13)
*Double-blind crossover study in 13 patients with asthma requiring high-dose (1500 mg) inhaled beclomethasone or
budesonide. McIvor RA et al Am J Respir Crit Care Med 1998;158:924-930.
Montelukast Provided Bronchoprotection without
Development of Tolerance
• In a clinical study, the bronchoprotective effect was significantly
diminished with time among patients taking salmeterol
Median
change from
baseline in
maximum
% decrease
in FEV1
(%)
80
70
Montelukast 10 mg once daily (n=97)
Salmeterol 50 mg twice daily (n=94)
p=0.015
p=0.002
60
50
40
30
20
10
0
Days 1–3
Week 4
Week 8
FEV1 = forced expiratory volume at one second
A 10-week randomised, double-blind trial of 191 patients with chronic asthma and documented exercise-induced
bronchoconstriction. After a 2-week placebo run-in, patients were randomised to montelukast 10 mg once daily or
salmeterol 50 mg 2 puffs twice daily for 8 weeks. Adapted from Edelman JM et al Ann Intern Med 2000;132:97-104 and
Data on file, MSD.
Montelukast Provided Protection against AMP Challenge
without Development of Tolerance
• In a clinical study, the bronchoprotective effect was significantly
diminished with time among patients taking salmeterol
Mean
AMP PC20
doubling
dose
difference
vs.
placebo
(pooled)
2.5
p<0.05
2.0
1.5
p=NS
1.0
0.5
0.0
Day 1
Week 2
Day 1
Week 2
(First dose) (Last dose) (First dose) (Last dose)
Salmeterol +
Montelukast +
inhaled corticosteroid
inhaled corticosteroid
Randomised, placebo-controlled, single-blind, double-dummy, crossover study of 20 patients with persistent asthma not
controlled on an ICS. For each 2-week active treatment period, patients received montelukast 10 mg once daily or salmeterol
50 mg twice daily in addition to their usual ICS. Adenosine monophosphate (AMP) challenge was performed after the first dose
of study medication and at the end of the 2-week treatment period. Adapted from Wilson AM et al Chest 2001;119:1021-1026.
Montelukast Did Not Reduce Rescue Effects of
Short-Acting Beta Agonists
• In a clinical study, response to short-acting beta agonist was
significantly diminished among patients taking salmeterol
Time to recovery following exercise challenge at week 1*
Patients
100
(cumulative
80
%)
p<0.05
p<0.05
p<0.05
p<0.05
60
40
Montelukast + fluticasone (n=39)
Salmeterol + fluticasone (n=39)
20
0
0
5
10
15
20
25
30
Time following rescue beta agonist (minutes)
A 6-week randomised, double-blind, double-dummy study of 122 adult patients with chronic asthma poorly controlled on
inhaled corticosteroids and a documented history of exercise-induced asthma. After a 2-week run-in, patients were randomised to
montelukast 10 mg once daily, inhaled salmeterol 50 mg twice daily, or placebo for 4 weeks in addition to fluticasone.
*Post-rescue recovery to pre-exercise FEV1 over time. Data on file, MSD.
Montelukast with a Steroid Targets
Dual Pathways of Inflammation
Montelukast
blocks the
effects of
cysteinyl
leukotrienes
Inhaled steroids
block
steroidsensitive
mediators
Complementary Effect
• Montelukast blocks the cysteinyl leukotriene pathway of
asthmatic inflammation
• Steroids do NOT inhibit the formation of cysteinyl leukotrienes
in the airways of patients with asthma
Artistic rendition
Montelukast with an Inhaled Steroid Provided Better
Control of Inflammation
p<0.05
Change from 0.12
baseline in
0.10
blood
eosinophil
0.08
counts
(x103/mL)
0.06
p<0.05
0.04
0.02
0
Placebo
(n=48)
Montelukast
(n=201)
Beclomethasone Montelukast +
(n=200)
beclomethasone
(n=193)
A 20-week randomised, double-blind, double-dummy clinical study of 642 adults (aged 15 years) with chronic asthma
incompletely controlled with inhaled corticosteroids. Adapted from LaViolette M et al Am J Respir Crit Care Med
1999;160:1862-1868.
IMPACT Study Objectives
• To assess the efficacy of 48 weeks of treatment with
montelukast vs. inhaled salmeterol concomitantly
administered with inhaled fluticasone on the primary
endpoint of percentage of patients with at least one
asthma exacerbation
• To determine the tolerability profile of both treatments
Bjermer L et al Respir Med 2000;94:612-621.
Country Participation
Investigators from 37 countries* 1490 patients included
*Participating countries in yellow
Inclusion Criteria
•
Aged 15–65 years
•
1-year history of chronic asthma
•
FEV1 50–90% of the predicted value
•
Improvement in FEV1 or PEF of 12% after beta agonist
•
Regular use of corticosteroids for 8 weeks prior to visit 1
•
Minimum predefined level of daytime symptoms (bi-weekly
score of 56) and beta-agonist use (average of 1 puff/day)
•
Current asthma treatment with only short-acting beta agonist
and inhaled corticosteroid
Bjermer L et al Respir Med 2000;94:612-621.
Study Design
Period I
Period II
Fluticasone
200 µg/day
n=747
Montelukast 10 mg/day +
fluticasone 200 µg/day + SP
MP + SP
n=743
Salmeterol 100 µg/day +
fluticasone 200 µg/day + MP
Visit 1
2
3
4
5
6
7
8
Week -4
-2
0
8
16
24
32
40
9
48
MP = montelukast placebo; SP = salmeterol placebo
Bjermer L et al Respir Med 2000;94:612-621.
Study Endpoints
Primary endpoint
•
Percentage of patients with at least one asthma exacerbation. An
asthma exacerbation was defined as worsening asthma requiring
an:
– unscheduled visit to the doctor’s office
– unscheduled visit to the emergency room
– unscheduled visit to hospital
– treatment with course of oral, intravenous or intramuscular
corticosteroids
Secondary endpoints included
•
Peripheral blood eosinophil counts, asthma-specific quality of
life, nocturnal awakenings, healthcare resource utilisation and
morning PEFR
In addition, the study compared the tolerability profiles of
montelukast and salmeterol in combination with inhaled
Bjermer L et al Respir Med 2000;94:612-621.
fluticasone
Percentage of Patients with No Asthma Exacerbations
Was Similar between Treatment Groups
100
Patients
with
no asthma
80
exacerbations
(%)
60
p=NS
79.9%
80.9%
Montelukast
+ fluticasone (n=747)*
Salmeterol
+ fluticasone (n=743)**
40
20
0
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg.
Modified-intention-to-treat approach. 20.1% and 19.1% of patients in the 2 groups, respectively, had 1 asthma exacerbation.
Bjermer L et al BMJ 2003;327:891-895.
Cumulative Percentage of Patients with an Asthma
Exacerbation Was Similar between Treatment Groups
Montelukast + fluticasone (n=747)*
Proportion 25
of patients
with
20
asthma
exacerbation
(%)
15
Salmeterol + fluticasone (n=743)**
10
p=NS
5
0
0
10
20
30
40
Weeks since randomisation
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg.
Bjermer L et al BMJ 2003;327:891-895.
50
Montelukast with Fluticasone Produced
Superior Reduction in Sputum Eosinophils
• In a substudy of 41 patients, montelukast significantly reduced a key
inflammatory marker in the airway
Change from 0.4
baseline in 0.3
mean
0.2
sputum
0.1
eosinophil
0
score
-0.1
(on 0–3
-0.2
scale)
-0.3
-0.4
-0.5
-0.6
-0.7
p=NS vs. baseline
19%
increase
40%
reduction
p<0.005 vs.
baseline
Montelukast +
fluticasone (n=25)*
Salmeterol +
fluticasone (n=16)**
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg. This sputum analysis was performed
for all patients participating in the IMPACT study at Finnish centres.
Bjermer L et al BMJ 2003;327:891-895.
Montelukast with Fluticasone Produced Superior
Reduction in Blood Eosinophils
Montelukast
+ fluticasone (n=747)*
Mean (SE)
0
change
from
-0.01
baseline
in blood
eosinophil -0.02
count
(x103/ mL)
-0.03
over
48 weeks
-0.04
-0.05
Salmeterol
+ fluticasone (n=743)**
-0.01 (0.01)
-0.04 (0.01)
p=0.011
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg. Values are least squares mean
change from baseline. P-value is for between-group difference. Baseline value = 0.3 x 103/mL in both treatment groups.
Bjermer L et al BMJ 2003;327:891-895.
Reduction in Nocturnal Awakenings from Baseline
Was Similar between Treatment Groups
Montelukast + fluticasone Salmeterol + fluticasone
(n=747)*
(n=743)**
Mean
change
from
baseline in
nights per
week with
awakenings
0
-0.5
-1
-1.5
-2
-1.68
p0.001
-1.74
p0.001
p=NS
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg. Values are least squares mean change
from baseline for overall treatment period. P-values indicate within-group change from baseline.
Bjermer L et al BMJ 2003;327:891-895.
Medical Resource Use Was Similar between
Treatment Groups
Montelukast +
fluticasone
(n=747)a
Salmeterol +
fluticasone
(n=743)b
Corticosteroid usec
15.8
14.4
Unscheduled visit to the doctord
11.0
10.8
Emergency room visit
2.8
2.8
Hospitalisation
0.7
0.9
Use of medical resources
(% patients)
10 mg + fluticasone 200 mg, bsalmeterol 100 mg + fluticasone 200 mg.
intramuscular, intravenous, or rectal. dTo medical specialist.
Bjermer L et al BMJ 2003;327:891-895.
aMontelukast
cOral,
Improvement in Asthma-Specific Quality of Life
Was Similar between Treatment Groups
Mean
1.0
change 0.9
from
baseline 0.8
(score) 0.7
0.6
p=NS
0.76
0.71
0.5
0.4
0.3
0.2
0.1
0.0
Montelukast + fluticasone
(n=747)*
Salmeterol + fluticasone
(n=743)**
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg. Values are least squares mean change from
baseline for overall treatment period. 0.5 represents the minimal important difference in Quality of Life Questionnaire score
(Juniper EF et al J Clin Epidemiol 1994;47:81-87.)
Bjermer L et al BMJ 2003;327:891-895.
Patients Receiving Montelukast with Fluticasone
Had Fewer Drug-Related and Serious Adverse Events
Montelukast Salmeterol p value
+ fluticasone + fluticasone
(n=747)*
(n=743)**
%
%
1 adverse event
71.0
72.4
p=NS
Drug-related adverse events***
6.3
10.0
0.010
Serious adverse events
4.6
7.4
0.022
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg.
***Determined by investigator to be possibly, probably or definitely drug related.
Bjermer L et al BMJ 2003;327:891-895.
IMPACT Findings
•
Combined therapy with montelukast and inhaled fluticasone
– was as effective as combined therapy with salmeterol in reducing the
number of asthma exacerbations
– significantly reduced inflammatory cells (sputum and blood
eosinophils)
•
Both treatments provided effective asthma control compared with
baseline
•
Both treatments were generally well tolerated, with less drugrelated and serious adverse events in the montelukast with
fluticasone group compared with salmeterol with fluticasone
Bjermer L et al BMJ 2003;327:891-895.
References
See notes page of PowerPoint file for references.
References (continued)
See notes page of PowerPoint file for references.
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