Transcript Additional Benefit of Montelukast in Patients with both

Additional Benefit of Montelukast in Patients
with Both Asthma and Allergic Rhinitis
Analysis from the COMPACT Trial
Price DB1, Swern AS2, Tozzi CA2, Philip G2, Polos P2, Yu Q2
Originally presented at the World Allergy Organization Congress (XVIII ICACI),
Vancouver, BC, Canada - September 10, 2003
Abstract published in Allergy & Clinical Immunology International 2003,
Suppl. 1:29 abstract O-15-1
1 General
Practice and Primary Care, University of Aberdeen, Aberdeen, UK
2 Merck & Co., Inc., Rahway, New Jersey, USA
Clinical Observation of
Montelukast as a Partner Agent
for Complementary Therapy
Price DB, Hernandez D, Magyar P et al. Thorax 2003;58:211-216
Background
 Asthma and allergic rhinitis frequently coexist1
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Rhinitis occurs in 75% of patients with allergic asthma and 80% of
patients with non-allergic asthma
The same triggers (e.g., allergens) can cause rhinitis and asthma
Actively treated rhinitis is a risk factor for asthma exacerbations1
 Upper and lower airways share a common & probably
interconnected inflammatory process
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Common inflammatory cells: mast cells, eosinophils, T-cells2
Common inflammatory mediators: histamine, leukotrienes, cytokines3
Bronchial challenge leads to nasal inflammation, and nasal challenge
leads to bronchial inflammation3
1. Price D, Thomas M. ERS 2002
2. Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334
3. Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001
Background
 Optimal management of rhinitis may improve
coexisting asthma1
 Montelukast is approved to treat asthma and
recently has gained approval for allergic rhinitis
in several countries
 Argentina, Czech Republic, Mexico, New Zealand,
United States, etc.
1. Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334
COMPACT Study Objectives
To determine the effect of:
 Adding montelukast to inhaled budesonide 800 mg daily
versus
 Doubling the dose of inhaled budesonide from 800 mg
daily to 1600 mg daily
Inclusion Criteria for COMPACT Study
 Adults (15 to 70 years) with chronic asthma for >1 year
 Using inhaled corticosteroids for >12 weeks
 Dose range: 600 to 1200 µg/day (of BDP or equivalent)
 Asthma not optimally controlled (judged by investigator)
 Baseline FEV1 or PEF value >50% predicted
 -agonist reversibility
 >12% in FEV1 or >15% in PEF at randomisation visit, or
 Predefined PEF variability >20%
 Minimal level of daytime symptoms and -agonist use during
the 2 weeks pre-randomisation
Study Design
Period II
Active treatment (12 weeks)
Double-blind
Period I
Run-in (4 weeks)
Single-blind
Montelukast 10 mg once daily
+
Budesonide 400 µg twice daily
Budesonide 400 µg
twice daily
n=448
Budesonide 800 µg twice daily
n=441
0
1
4
8
Weeks
12
16
Objective of this Analysis
 To determine if treatment with montelukast
added to budesonide (400 mg twice daily),
compared with budesonide (800 mg twice
daily), provides additional benefit to patients
with co-existing asthma and allergic rhinitis
Statistical Analysis
 All patients with a baseline and at least one on-treatment
value were included in this intention-to-treat analysis
 Treatment comparisons were based on an analysis of
covariance (ANCOVA) model, with corresponding
baseline value included as a covariate and treatment
group as a factor
 All analyses of patient subgroups were post hoc
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
Patient Demographic Characteristics
Asthma+AR Asthma–AR
N=410
N=479
Age, years
median (range) 43 (15-74)
45 (15-75)
Race, n (%)
Caucasian
Black
Hispanic
Other
319 (77.8)
4 (1.0)
46 (11.2)
41 (10.0)
365
2
82
30
171 (41.7)
239 (58.3)
184 (38.4)
295 (61.6)
Gender, n (%) Male
Female
(76.2)
(0.4)
(17.1)
(6.3)
Patient History
Asthma+AR
N=410
Age when asthma first treated, years
Asthma–AR
N=479
23 (0.1-70)
28 (0- 71)
15 (0-65)
13 (0-59)
337 (82.6)
384 (80.2)
79 (19.3)
58 (12.1)
All year long without seasonal flares
25 (36.2)
18 (37.5)
Only during certain seasons
28 (40.6)
21 (43.8)
All year with seasonal flares
16 (23.2)
9 (18.8)
305 (74.4)
275 (57.9)
median (range)
Duration of asthma, years
median (range)
History of exercise-induced asthma
n (%)
History of atopic dermatitis, n (%)
Skin tested for allergies, n (%)
Patient Baseline Characteristics
Asthma+AR
N=410
Asthma–AR
N=479
AM PEF
median (range)
381 (89-870)
360 (62-875)
Eosinophils
median (range)
0.24 (0-1.59)
0.23 (0-2.12)
Using Rhinitis Meds Prestudy
Intranasal steroid (INS)
Antihistamines (A)
Other treatments (O)
INS or A or O
n (%)
14 (3.4)
41 (10.0)
12 (2.9)
57 (13.9)
n (%)
9 (1.9)
15 (3.1)
10 (2.1)
30 (6.3)
Change in AM PEF
Total Group
Change from Baseline
(L/Min, LS Mean ± SEM)
50.0
40.0
30.0
p=0.36
20.0
Montelukast* (N=433)
10.0
Budesonide** (N=425)
0.0
4
8
Weeks
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
12
Change in AM PEF
Total Group
Montelukast*
Budesonide**
AM PEF values
N=433
N=425
Baseline (L/min)
391.0
388.5
Absolute increase (L/min)
33.5
30.1
Percent increase (%)
8.6%
7.7%
Difference for
Montelukast–Budesonide
(L/min)
Least Squares Mean (95% CI)
4.2 (-4.7, 13.0)
P=0.357
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
Change in AM PEF
Asthma+AR Patient Group
Post Hoc Analysis
Changes from Baseline
(L/Min, LS Mean + SEM)
50.0
40.0
30.0
p<0.03
20.0
Montelukast* (N=216)
10.0
Budesonide** (N=184)
0.0
0
8
4
Weeks
* Montelukast 10 mg once-daily with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
12
Change in AM PEF
Asthma+AR Patient Group
Montelukast*
Budesonide**
AM PEF values
N=216
N=184
Baseline (L/min)
394.7
403.4
36.4
24.1
Absolute increase (L/min)
Percent increase (%)
9.2%
6.0%
Difference for
Montelukast–Budesonide
(L/min)
Least Squares Mean (95% CI)
14.2 (1.58, 26.84)
P=0.028
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
Change in AM PEF
Asthma+AR Patients: Using Rhinitis Meds§
Post Hoc Analysis
70.0
Changes from Baseline
(L/Min, LS Mean + SEM)
60.0
50.0
40.0
p<0.02
30.0
20.0
10.0
0.0
-10.0
-20.0
4
8
Weeks
12
Montelukast* (N=33)
Budesonide** (N=23)
§ Intranasal steroids or antihistamines or other treatments for rhinitis
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
Change in AM PEF
Asthma+AR Patients: Using Rhinitis Meds
Montelukast*
Budesonide**
AM PEF values
N=33
N=23
Baseline (L/min)
431.1
411.9
52.1
7.8
12.1%
1.9%
Absolute increase (L/min)
Percent increase (%)
Difference for
Montelukast–Budesonide
(L/min)
Least Squares Mean (95% CI)
44.3 (8.35, 80.25)
P=0.017
§ Intranasal steroids or antihistamines or other treatments for rhinitis
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
§
Percent Increase in AM PEF
in Different AR Subgroups
Montelukast*
N
Percent
Budesonide**
N
Percent
Total Patients
433
8.6%
425
7.7%
Asthma+AR Patients
216
9.2%
184
6.0%
33
12.1%
23
1.9%
Asthma+AR Patients Using
Rhinitis Meds §
Percentages calculated using LS mean for change and baseline mean
§ Intranasal steroids or antihistamines or other treatments for rhinitis
* Montelukast 10 mg once-daily along with budesonide 400 mg twice-daily.
** Budesonide 800 mg twice-daily
Results
 Adding montelukast significantly improved AM PEF in
patients who had both asthma and allergic rhinitis
(defined by both patient history and physician diagnosis),
versus doubling the dose of inhaled budesonide
 Treatment effect was greatest in patients taking medications for
rhinitis at randomization
 Doubling the dose of budesonide was less effective for
asthma than adding montelukast in patients with both
allergic rhinitis and asthma
 Patients with both allergic rhinitis and asthma – who were also
taking medications for rhinitis – showed minimal improvement in
AM PEF with doubling the budesonide dose
Conclusion

In the subgroup of patients from the COMPACT study
who had both asthma and allergic rhinitis, adding
montelukast to budesonide provided greater benefit in
reducing airflow obstruction, compared with doubling the
dose of budesonide
Acknowledgment
The authors express gratitude to the study centers and investigators:
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Argentina: Baena-Cagnani CE, Lopez AM, Nannini LJ, Neffen H, Callejas O, Rey CA, Rojas R, Taborda J
Australia: Bryant D, Dennis C, Holmes P
Austria: Eckmayr J, Kummer F, Obermair H, Roger MG, Vetter N, Wanka W, Wild M, Wildner C, Zwick H
Belgium: Dierickx H, Mestdagh J, Rombouts L, Schatteman E, Schoofs H
Brazil: Fiterman J, Barreto SM
Canada: Laviolette M
China: Lin J, Luo W, Zhong NS, Zhou X
Colombia: Naranjo F
Finland: Rossi O, Toljamo T, Torkko M
Germany: Becker J, Beeh KM, Harnest U, Linnhoff A, Mikloweit P, Mitlehner W, Schmidtmann S, Schultebraucks R,
Seevers C, Stutz P
Greece: Christaki P, Gaga A, Galanis N, Gourgoulianis G, Cratsiou C, Konstantopoulos S, Papadakis NE,
Papageoriou G, Siafakas N
Hungary: Baliko Z, Berta G, Csontos Z, Herjavecz I, Kraszko P, Nekam K, Namenyi M, Magyar P, Szuks Z
Italy: Centanni S, Di Maria GU, Fabbri LM, Schmid G
Mexico: Acuna M, Hernandez D, Perez R, Salazar R
Netherlands: Aalbers R, Bantje T, Bax AJM, Creemers JPHM, Harreveld A, Van Kralingen K, Kuipers A, Luursema P,
Van Noord J, Rijssenbeek-Nouwens LHM, Sinninghe Damst HEJ, Van Weelden BM, Wever AMJ
Norway: Bergmann A, Johansen B, Langaker KE
Portugal: Almeida J, Arrobas AM, Miranda MS, Segorbe AL
Romania: Radu JR, Stoicescu IP
Spain: Ercoreca IA, Hernandez JC, Olaguibel-Rivera JM, Pelaez A, Prieto-Andres JL, Reques FG, Rodriguez JR,
Sanz CC
Sweden: Johansson G, Lind A, Lundback B, Spjuth A
Switzerland: Graf HJ, Gumowski P, Pons M, Spertini F
Taiwan: Chiang CD, Wang JH
UK: Barnes N, Corris P, O’Connor B, Dilworth P, Fahmy M, Fletcher P, James IB, Price DB
Venezuela: Montes De Oca MDC
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