sga 2003-w-286751-ss slide 1 capacity of oral singulair to prevent asthma exacerbations capacidad de...

SGA 2003-W-286751-SS Slide 1

Capacity of Oral SINGULAIR to Prevent Asthma Exacerbations

CApacidad de SIngulair™ Oral en la Prevencion de

Exacerbaciones Asmaticas

SINGULAIR (montelukast sodium) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

SGA 2003-W-286751-SS Slide 2

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; Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; discussion S43-S48; LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868; Bisgaard H Allergy 2001;56(suppl 66):7-11.

• Rationale– Leukotrienes are powerful inflammatory mediators

that are not blocked by steroids in the airways of asthmatic patients

– LTRAs can further reduce inflammation and improve symptoms when added to ICS therapy

• Additive effects on peripheral blood eosinophils, a marker of inflammation, shown in clinical studiesof LTRAs + ICS

– Effects of ICS + leukotriene-modifying treatment on reducing asthma exacerbations, a prominent goal of asthma therapy, must be evaluated

• Objective – To evaluate the addition of oral montelukast to

patients’ usual dose of inhaled budesonide in the treatment of adults with mild to moderate asthma

Rationale and Objective

SGA 2003-W-286751-SS Slide 3

PEFR = peak expiratory flow rate

Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.

CASIOPEA Study

Primary Endpoint

% of Asthma Exacerbation Days

Defined as a day when any of the following occurred

• Awake all night (awake all night or recurrent episodes of awakening)

• Increase from baseline in symptom score of >50%

• Increase from baseline in beta-agonist use of >70% (minimum increase 2 puffs/day)

• Decrease from baseline of >20% in morning PEFR

• Morning PEFR <180 l/min

• Asthma attack (unscheduled medical care for asthma)

SGA 2003-W-286751-SS Slide 4

Budesonide Turbuhaler 400–1600 µg qd

+ montelukast (n=326)

Budesonide Turbuhaler 400–1600 µg qd

+ placebo

(n=313)

qd = once daily

Inhaled short-acting beta2 agonists were permitted as needed.


CASIOPEA Study

Design

Period I

Weeks

Period II

Budesonide Turbuhaler

400–1600 µg/day

V1–2

V20

V24

V28

V516

SGA 2003-W-286751-SS Slide 5

FEV1 = forced expiratory volume in one second


• Non-smoking asthmatic patients 18–70 years of age

• Prior treatment with a clinically stable dose of ICS equivalent to budesonide 400–1600 µg/day

• FEV1 55% of predicted

• Reversible airway obstruction (12% increase from baseline)

• Minimum total daytime asthma symptom score of 64 (of possible 336)

1 puff/day of beta2 agonist

CASIOPEA Study

Inclusion Criteria

SGA 2003-W-286751-SS Slide 6

*Mean ± SD **Mean of scores to four questions, each rated on a scale of 0 (best) to 6 (worst)***44 (14%) and 35 (11%) patients on placebo and montelukast, respectively, received 400 µg/day


Montelukast Budesonide + Budesonide

(n=313) (n=326) Age, yr (range)* 44 ± 16 (18–79) 42 ± 15 (18–76)Gender, no.

Female 121 (39%) 124 (38%) Male 192 (61%) 202 (62%)

Duration of asthma, year* 13.8 ± 11.7 13.8 ± 11.4% of predicted FEV1* 81 ± 21 81 ± 19

Morning PEFR (L/min) 365 ± 108 373 ± 105Evening PEFR (L/min) 375 ± 108 382 ± 107Daytime asthma symptom score*,** 2.3 ± 0.8 2.2 ± 0.8Beta2-agonist use (puffs/day)* 3.3 ± 2.3 3.2 ± 2.5

Budesonide dose (µg/day), no.*** I. 400–800 202 (66%) 219 (69%) II. 801–1200 15 (5%) 18 (6%) III. 1201–1600 91 (30%) 80 (25%)

CASIOPEA Study

Baseline Characteristics of Patients

SGA 2003-W-286751-SS Slide 7


CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Asthma-Exacerbation Days

4.8

3.1

Budesonide + placebo (n=308)

Montelukast + budesonide

(n=317)

Medianpercentageof asthma-

exacerbation days

5

4

3

2

1

0

35%p=0.03

SGA 2003-W-286751-SS Slide 8

p=0.67 (ns) across strata

Adapted from additional analysis of CASIOPEA study: asthma exacerbation days per budesonide dose strata and onset of action for beta agonist use

Regardless of ICS dose

CASIOPEA Study

Montelukast + Budesonide Reduced Asthma-Exacerbation Days

10

8

6

4

2

0

No. ofasthma

exacerbationdays

I (n=421)

Budesonide + placeboMontelukast + budesonide

II (n=33)

III (n=171)

Strata of ICS dose

SGA 2003-W-286751-SS Slide 9


CASIOPEA Study

Montelukast + Budesonide Significantly Increased Asthma-Free Days

42.3

66.1



(n=317)

Medianpercentageof asthma-free days

70

60

50

40

30

56%p=0.001

SGA 2003-W-286751-SS Slide 10

*The percentage of patients who awoke during the night because of asthma


CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Nocturnal Awakenings

25.6

Least square mean % of

patientswith nocturnalawakenings*

35

30

25

20

32.2

20%p=0.01



(n=317)

SGA 2003-W-286751-SS Slide 11

*p = 0.05 vs. budesonide alone


CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Beta2-Agonist Use*

% changefrom

baseline inbeta2-agonist

use

30

20

10

0

–10

–20

–30

–40

First 7 days in active treatment

Budesonide + placebo (n=313)Montelukast + budesonide (n=326)

Basal 1 2 3 4 5 6 7

A more rapid onset of action than budesonide + placebo

SGA 2003-W-286751-SS Slide 12

CASIOPEA Study

Montelukast + Budesonide Significantly Increased AM PEFR*

Tertiary endpoint: Morning PEFR

Mean adjusted by center and stratum

*p = 0.05 vs. budesonide alone


11.3

16.86



(n=317)

20

15

10

5

0

49%p=0.05

Least square mean change

in morningPEFR

(L/min)

SGA 2003-W-286751-SS Slide 13

% of Patients Most Common Budesonide + Montelukast + Adverse Events placebo (n=313) budesonide (n=326) Influenza 11 12Headache 9 11Upper respiratory infection 7 5Worsening asthma 5 7Epigastric pain/pyrosis 2 3Urinary tract infection 2 2Rhinitis 2 2Pharyngitis 1 2Bronchitis 1 2Total 41 44

No significant differences between groups


Montelukast + Budesonide Was Well Tolerated

Incidence of adverse events comparable to budesonide + placebo

SGA 2003-W-286751-SS Slide 14


• Montelukast added to patients’ usual dose of budesonide significantly improved asthma control (p0.05)– Effective control regardless of patients’

budesonide dose

• Faster onset of action than budesonide + placebo, evident from day 1

• Montelukast + budesonide was well tolerated, with a tolerability profile comparable to budesonide + placebo

CASIOPEA Study

Summary

Montelukast provided effective asthma control

SGA 2003-W-286751-SS Slide 15

Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Currie GP et al Am J Respir Crit Care Med (in press); LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868; Bisgaard H Allergy 2001;56(suppl 66):7-11; Vaquerizo MJ et al Thorax 2003;58:204-211.

Conclusions

• CysLTs and steroid-sensitive mediators comprise dual pathways of inflammation in asthma

• Corticosteroids at any dose do not block leukotrienes in the airways of asthmatic patients

• In clinical studies, complementary therapy with the LTRA montelukast and ICS effectively reduced inflammation and improved symptom control in patients with mild to moderate persistent asthma

SGA 2003-W-286751-SS Slide 16

References

Please see notes page.

SGA 2003-W-286751-SS Slide 17

CApacidad de SIngulair™ Oral en la Prevencion de Exacerbaciones Asmaticas

Capacity of Oral SINGULAIR to Prevent Asthma Exacerbations

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. Printed in USA

VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com

sga 2003-w-286751-ss slide 1 capacity of oral singulair to prevent asthma exacerbations capacidad de...

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