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The Effect of Montelukast on Rhinitis Symptoms in Patients With Asthma and Seasonal Allergic Rhinitis

Posted on: Saturday, 18 December 2004, 03:00 CST

Key words: Allergic rhinitis - Asthma - Concomitant allergy and asthma - Daily Rhinitis Symptoms Daytime Nasal Symptoms - Montelukast - Upper and lower airway disease

SUMMARY

Objective: The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season.

Methods: This was a multicenter study of 831 patients (ages 15years-85years) with seasonal allergen sensitivity, active symptoms of seasonal allergic rhinitis, and active asthma. Following a single- blind, placebo run-in period of 3days-5days, patients were randomized to oral montelukast 10 mg (n = 415) or placebo (n = 416) daily during the 2-week, double-blind, activetreatment period.

Main outcome measures: The primary endpoint was Daily Rhinitis Symptoms score, average of Daytime Nasal Symptoms and Nighttime Symptoms, as self-rated by patients on a 0-3 scale on daily diaries.

Results: Montelukast reduced the Daily Rhinitis Symptoms score: difference between montelukast and placebo in mean change from baseline was -0.12 [95% Cl -0.18, -0.06; p < 0.001], Similar improvements were seen in Daytime Nasal Symptoms (-0.14 [-0.21, - 0.07; p < 0.001]) and Nighttime Symptoms (-0.10 [-0.16.-0.04; p < 0.001]). Improvements (p < 0.05) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician, and Rhinoconjunctivitis Quality of Life. In exploratory analyses, improvement in rhinitis symptoms was numerically (though not statistically) larger in patients with greater levels of asthma at study start. Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician: mean differences were -0.24 [-0.41,-0.06; p =0.008] and - 0.17 [-0.33-0.01; p= 0.037]. Similarly, as-needed β-agonist use (puffs/day) was reduced with montelukast (p < 0.005).

Conclusion: Montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma.

Introduction

Asthma and allergic rhinitis are often co-morbid diseases. Asthma is estimated to affect approximately 4%-ll% of the general population while allergic rhinitis is estimated to affect 10%- 30%1,2. Twenty to forty per cent of patients with allergic rhinitis are reported to have concomitant asthma, while 30%-90% of patients with asthma are reported to have concomitant allergic rhinitis31. Aspects of the underlying pathology that are common to both diseases are striking. Both conditions are characterized by inflammation of the respiratory mucosa, and are associated with the same allergic and pro-inflammatory mediators such as histamine, leukotrienes and cytokines from allergen-activated mast cells, eosinophils and Th2 lymphocytes5,6. Local allergen exposure may result in generalized airway inflammation, suggesting linked inflammatory pathways in the respiratory mucosa. Thus, tissue eosinophilia, a characteristic of allergic inflammation7, is seen in the upper and lower airways following nasal allergen provocation in non-asthmatic patients with seasonal allergic rhinitis8. Conversely, segmental bronchial provocation in non-asthmatic allergic rhinitis patients caused allergic inflammation in the nose, while also inducing nasal and chest symptoms as well as reducing nasal and pulmonary function9.

A key role for cysteinyl leukotrienes in mediating both asthma and allergic rhinitis is supported by the recovery of these inflammatory mediators from bronchoalveolar and nasal lavage fluids during allergeninduced reactions, both following allergen challenge as well as in natural disease10 '2. Cysteinyl leukotrienes are known mediators of smooth muscle contraction (in the lower airway), increased blood flow (in the upper airway), mucus secretion, plasma exudation, and inflammatory cell activation13 IS. Therefore, based on common and possibly linked pathophysiology in lower and upper airways, it is likely that blocking the cysteinyl leukotriene receptor will provide benefit to patients who have clinical evidence of both asthma and allergic rhinitis10,16.

Asthma and allergic rhinitis each place a considerable burden on patients and on society. Asthma is associated with significant health resource costs, including hospitalization, and is sometimes fatal. Although allergic rhinitis is not life threatening, it is bothersome for affected patients, negatively impacts quality of life, and may impair workplace performance. In patients with comorbid disease, not only is the symptomatic burden of allergic rhinitis added to that of asthma, but poorly managed allergic rhinitis may also complicate management of asthma and may be associated with poor asthma outcomes17.

The cysteinyl leukotriene type 1 receptor antagonist, montelukast, has demonstrated clinical benefit in patients with persistent asthma18,19 and in patients with seasonal allergic rhinitis20-24. In contrast to the present study, previous seasonal allergic rhinitis studies of montelukast did not specifically enroll patients with persistent asthma, as inhaled corticosteroid use was a study exclusion. Since concomitant allergic rhinitis constitutes a substantial burden in patients with asthma, we evaluated the efficacy of montelukast in improving symptoms of seasonal allergic rhinitis in a study population with active asthma (including patients using inhaled corticosteroids for asthma) and active seasonal allergic rhinitis.

Patients and methods

This randomized, parallel-group, double-blind, doubledummy study was performed during spring and fall of 2003 (52 centers in US and Europe). Following a singleblind placebo run-in period of 3 days-5 days, patients were randomized (using a computer-generated schedule) to oral montelukast 10mg (n = 415) or placebo (n = 416) daily at bedtime during the 2-week active-treatment period. Patients, 15years- 85years old, had a > 1-year clinical history of active asthma (including dyspnea, wheezing, chest tightness, cough) and a > 2- year clinical history of seasonal allergic rhinitis (rhinitis symptoms exacerbating during allergy season). Eligible patients had to demonstrate Daily Rhinitis Symptoms (defined below) at least mild- to-moderate in severity during the placebo run-in period. Patients had to demonstrate a positive skin test (wheal diameter > 3 mm greater than control) to > 3 allergens active during the study season. Patients also had to meet > 1 of 4 criteria for active asthma: asthma symptoms > once weekly, on average, during the 4 weeks before the first visit; reversible airway obstruction (> 12% increase in forced expiratory volume in l s (FEV1) after inhaled short-acting β-agonist); history of methacholine hyperresponsiveness; > 1 -year history of exercise-induced bronchoconstriction. Patients on a stable dose of inhaled corticosteroid and/or inhaled long-acting β-agonist were eligible. Other confounding disorders, and medications for allergic rhinitis, conjunctivitis, ocular and other nasal symptoms, and other medications for asthma were not allowed: these included antihistamines and decongestants; oral, parenteral, nasal, and ophthalmic corticosteroids; cromolyn sodium, nedocromil, theophyllinc, and inhaled anticholinergics; antileukotrienes such as zafirlukast and zileuton; and oral β-adrenergic agonists.

Patients completed a daily diary during the run-in and treatment periods and scored each symptom on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe symptoms). The primary endpoint was the Daily Rhinitis Symptoms score, defined as the mean of two components: Daytime Nasal Symptoms score (average of nasal congestion, rhinorrhea, sneezing, and itching, each rated on a 0-3 scale) and Nighttime Symptoms score (average of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings, each rated on a 0-3 scale). Also measured was the Daytime Eye Symptoms score (average of the individual symptoms of tearing, itching, red and puffy eyes). These diary-based endpoints have been previously reported20-24.

The secondary endpoint of Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ)25'26 overall score was completed by patients, using a 6-point scale, before randomization and at the end of the 2- week treatment period. The overall score is the average of the scores of seven individual domains: nasal symptoms, eye symptoms, non-nose/eye symptoms, activity, sleep, emotions, and practical problems. The two other secondary endpoints were the Global Evaluations of Allergic Rhinitis by Patient and by Physician; each evaluation was a single question, using a 6-point scale, which assessed the clinical status of allergic rhinitis at the end of the treatment period relative to study entry. Additional endpoints included Global Evaluations of Asthma by Patient and by Physician (which assessed asthma clinical status at the end of the treatment period), and as-needed use of the short-acting -agonist (SABA) during treatment (recorded on daily diaries), as well as the individual symptoms/domains of the primary endpoint and RQLQ (see Results). Compliance was assessed by comparing the number of days that each study drug was taken with the number of days in eac\h treatment period.

Figure 1. Patient disposition

Safety analysis included all randomized patients who received at least one dose of study therapy. Safety and tolerability were assessed by monitoring patients for adverse events throughout the run-in and treatment periods. Clinical adverse experiences were assessed and recorded at each clinic visit. After baseline laboratory samples for blood cell counts, serum chemistry and urinalysis were collected prior to the run-in period, any subsequent laboratory testing was performed only at the discretion of the investigator.

The study was approved by ethical review committees for each study site and all patients gave written informed consent before any study procedure was performed.

Table 1. Baseline characteristics

Statistical Analysis

Moan symptom scores wore calculated at baseline and over the 2 weeks of double-blind treatment. For the diary- and RQLQ-based endpoints, changes from baseline were compared between the two treatment groups in an ANCOVA (analysis of covariance) model (with the baseline value as covariate). For the global evaluations, between-treatment comparisons were based on an analysis of variance model. Treatment differences were expressed for all endpoints as leastsquares (LS) means and 95% confidence intervals (CI). Adjustment for multiplicity testing was predefined for the primary endpoint and the three secondary endpoints. Post hoc subgroup analyses (by asthma status at study start) and analyses of as- needed use of SABA were based on ANCOVA models. Pearson correlation coefficients were calculated between measures of rhinitis and asthma.

The study was designed such that for a sample size of 380 patients per treatment group, it had a 90% power to detect a treatment difference of-O. If score (assuming a standard deviation of 0.46) between the two groups for the primary endpoint of Daily Rhinitis Symptoms

Results

Baseline Characteristics

Of 1255 patients screened, 831 were randomized and 799 completed the study (Figure 1). Baseline patient characteristics, including demographics, allergic history, and baseline efficacy scores are listed in Table 1. The mean age of patients was 33.3 years, and most were women (64%). The mean duration of allergic rhinitis was 19.3 years, and the mean duration of asthma was 17.0 years. Patients were mild-to-moderate asthmatics, with a mean percentage-predicted FEV1 (prebronchodilator) of 84.0%. About 41% of patients were using inhaled corticosteroids at baseline. Baseline efficacy measures as well as the baseline use of corticosteroids were similar between the montelukast and placebo treatment groups (Table ]). There were no clinically meaningful differences between the treatment groups for any baseline characteristic.

Figure 2. Mean change from baseline in symptom scores for the primary endpoint of Daily Rhinitis Symptoms and its two main components, averaged over the 2-week double-blind treatment. Percentages within each bar represent the median percentage change in scores from the baseline

Table 2. Efficacy results. A. Scores from daily symptom diaries. B. secondary and other efficacy endpoints

Efficacy

Montelukast demonstrated significant efficacy over the 2-week double-blind treatment period in improving symptoms of seasonal allergic rhinitis in patients with co-morbid, active asthma. Montelukast significantly reduced the primary endpoint of Daily Rhinitis Symptoms score, compared with placebo (p < 0.001) (Table 2A and Figure 2). While a large placebo effect was seen, this is an expected finding in allergic rhinitis studies in which the endpoints are subjective; nonetheless, treatment differences between montelukast and placebo were significant. Montelukast also showed significantly greater effect than placebo on the two main components of the primary endpoint, the Daytime Nasal Symptoms score (p < 0.001) and Nighttime Symptoms score (p < 0.001). The effect of montelukast was significantly larger than that of placebo on the three secondary endpoints, the Rhinoconjunctivitis Qualityof-Life overall score (p = 0.002), the Global Evaluation of Allergic Rhinitis by Patient, and the Global Evaluation of Allergic Rhinitis by Physician (eachp < 0.001 vs. placebo) (Table 2A and B). Significant improvements relative to placebo were also seen in the Daytime Eye Symptoms score (p = 0.02), in three of the four individual items of the Daytime Nasal Symptoms score (nasal congestion, rhinorrhea, sneezing; all p < 0.003), in one of the three items of the Nighttime Symptoms score (nasal congestion upon awakening; p < 0.001), in one of the four items of the Daytime Eye Symptoms score (tearing eyes; p < 0.001), and in six of the seven individual quality-of-life domains of the RQEQ (nasal symptoms, eye symptoms, activity, sleep, emotions, and practical problems; eachp < 0.05).

Figure 3. Treatment effect of montelukast (shown as the difference from placebo) on the Daily Rhinitis Symptoms score, as estimated within subgroups based on asthma status at study start

In additional efficacy endpoints specifically measuring asthma, montelukast provided significant benefit, relative to placebo, in the Global Evaluations of Asthma by Patient and by Physician (eachp < 0.05) (Table 2B). Analyses that assessed as-needed SABA use during treatment showed that montelukast significantly reduced the number of puffs per day of SABA use, both in the complete study cohort and in the subgroup of patients who had as-needed SABA use during the baseline run-in period (p < 0.005) (Table 3). Furthermore, a separate subgroup analysis showed that montelukast was significantly more effective in reducing the number of as-needed SABA puffs per day in patients whose FEV1 reversibility to SABA was > 12% (Table 3).

Subgroup analyses explored the effect of montelukast on allergic rhinitis in patients categori/ed by their asthma status at study entry (as in Figure 3). The effect of montelukast was consistent across the various subgroups (i.e., treatment-by-subgroup interactions were not statistically significant), though a trend was noted for improvement in rhinitis symptoms to be larger in patients with greater levels of asthma at study entry. The subgroup of patients on inhaled corticosteroids at study entry showed a significant improvement on montelukast, compared with placebo, in their Daily Rhinitis Symptoms; the mean treatment difference and 95% CI (montelukast minus placebo) was -0.16 (-0.26, -0.05) (Figure 3). Similarly, the patients with asthma symptoms at least twice weekly at study entry showed significant improvement in Daily Rhinitis Symptoms (-0.15 (-0.23, -0.08)), as did the patients with spirometry results that suggested a greater burden of asthma (-0.15 (-0.26, - 0.04)) (Figure 3). The treatment difference between montelukast and placebo in each of these subgroups, was numerically (though not statistically) larger than the treatment difference of -0.12 seen in the entire population.

Table 3. Short-acting β-agonist (SABA) use during treatment

Exploratory correlation analyses between the levels of asthma at study entry and the baseline daily rhinitis symptoms yielded very low correlation coefficients (each < 0.10) that were not significant (data not shown). However, the improvements in the global evaluations of allergic rhinitis and of asthma were highly correlated (correlation coefficients in the montelukast group of 0.67 and 0.70 for the global evaluations by patients and by physicians, respectively; each p < 0.001).

Mean compliance was 99.4% in the montelukast group and 99.3% in the placebo group.

Safety

Clinical adverse experiences occurred in 49 (11.8%) and 54 (13.0%) patients in the montelukast and placebo treatment groups, respectively. The most frequently reported adverse experiences (> 1% incidence) were: in the montelukast treatment group - rash, 5 (1.2%) and headache, 4 (1.0%); in the placebo treatment group headache, 8 (1.9%); sinusitis, 5 (1.2%); nasopharyngitis, 5 (1.2%); and dry mouth, 4 (1.0%). There were no clinically meaningful differences and no statistically significant differences between treatment groups in the incidence of clinical adverse experiences. Discontinuations due to adverse experiences were infrequent and comparable between the montelukast and placebo treatment groups (Figure 1). No laboratory adverse experiences were reported during this study.

Discussion

The current understanding of the shared pathological basis, co- morbid health impairments, and higher socioeconomic costs of asthma and allergic rhinitis has culminated in the Allergic Rhinitis in Asthma (ARIA) guidelines. These guidelines recommend that asthmatic patients be evaluated for allergic rhinitis, and that rhinitis patients be evaluated for asthma27'28. An integrated therapeutic approach has been proposed that recommends that asthma and allergic rhinitis be viewed as clinical expressions of the same inflammatory disease and that treatment of both upper and lower airways should consequently be combined. This clinical approach is predicated on the general recognition that asthma and allergic rhinitis are systemically linked by common and interrelated inflammatory processes of the upper and lower airways27'29'30.

In addition to the symptomatic burden of allergic rhinitis in patients with asthma3', allergic rhinitis can complicate management of asthma and result in poor asthma outcomes. In an exploratory analysis of the IMPACT study of asthma32, concomitant allergic rhinitis, present in a substantial subset (60%) of patients, was associated with a higher risk of emergency department visits (odds ratio = 2.2; 95% CI 1.1-4.5) and asthma attacks (odds ratio = 1.3; CI 1.04-1.71)33. In addition, asthmatic patients with allergic rhinitis appear to have more asthma-related healthcare resource use, as shown in a UK general practice database study: adult asthmatic patients with allergic rhinitis had a significantly increased risk \of hospitalization for asthma (odds ratio = 1.52, 95% CI 1.03, 2.24) and had significantly (p < 0.001) higher use of SABA and oral corticosteroids over a 1-year period compared to asthmatics without concomitant allergic rhinitis3'1. Similarly, in a retrospective, cross- sectional study in Germany, treatment costs rose, in conjunction with asthma severity, in patients who also had seasonal allergic rhinitis35.

While the burden of concomitant allergic rhinitis in patients with asthma is substantial, few therapeutic options are available that treat both disorders. Corticosteroids have been the mainstay of therapy for asthma and allergic rhinitis. However, because of side effects associated with systemic corticosteroids, this therapy is usually topical and requires separate administration of an inhaled corticosteroid for asthma and an intranasal corticosteroid for allergic rhinitis. Recently, a number of papers have advocated a key role for cysteinyl leukotriene receptor antagonists in the treatment of concomitant allergic rhinitis and asthma1"1'629. Furthermore, in patients with asthma and allergic rhinitis, montelukast as well as combination inhaled/intranasal budesonide significantly reduced allergic rhinitis symptoms and showed comparable efficacy on the lower airway3''.

In studies with antihistamincs in patients with asthma and allergic rhinitis, both desloratadine and montelukast improved asthma symptoms37, while cetirizine or desloratadine when added to montelukast were both effective in reducing nasal symptoms111.

In this study, montelukast significantly reduced daytime and nighttime symptoms of allergic rhinitis in patients with asthma, as measured by the primary endpoint of Daily Rhinitis Symptoms score. Each secondary endpoint was positive, as well: patients on montelukast had significant improvements in rhinoconjunctivitis- specific quality of life, compared with placebo, and significant improvements in the global evaluations of allergic rhinitis, as evaluated separately by the patient and by the physician. These results are consistent with those demonstrated for montelukast in previous studies of seasonal allergic rhinitis2024.

Objective lung function measures, such as FEV1, were not used to measure asthma efficacy in this study as it was primarily focused on rhinitis efficacy. Nevertheless, montelukast did provide significant relief from asthma, as measured broadly in global evaluations of asthma by both the patient and the physician. Furthermore, although as-needed usage of SABA was low at baseline in this mild-to- moderate population, post hoc analyses showed that montelukast was significantly more effective than placebo in reducing the average number of puffs per day. Reduced as-needed SABA usage while on montelukast was observed in the complete study cohort, in the subgroup of patients who had used SABA during the baseline period, and in the subgroup with β-agonist reversibility > 12%. This effect was observed even though there was no specific enrollment of patients with high SABA use. The results reported here are consistent with the beneficial effects of montelukast previously shown in studies designed specifically to assess mild to moderate persistent asthma18-39.

While montelukast provided significant improvement of rhinitis symptoms when averaged over all patients in this study, it may have particular benefit for rhinitis in those patients with more pronounced asthma, as assessed by a variety of asthma measures at study start. Patients requiring inhaled corticosteroids, those with asthma symptoms at least twice weekly, those with baseline FEV1 < 80%-predicted, or those with β-agonist reversibility of > 12%, showed a trend toward greater improvements in their Daily Rhinitis Symptoms score when treated with montelukast. Furthermore, a concomitant benefit of montelukast on allergic rhinitis and asthma was suggested by the strong correlation in improvements in global evaluations of allergic rhinitis and of asthma (as reported by patients and physicians at the end of the study), despite poor correlation of allergic rhinitis and asthma measures at baseline.

Other available data suggest a greater benefit of cystcinyl leukotriene antagonism in patients who have concomitant asthma and allergic rhinitis. An exploratory analysis of the COMPACT study40 of patients with persistent asthma showed that a subgroup of patients with a physician-confirmed history of allergic rhinitis had a greater increase in lung function after adding montelukast to budesonide 800 μg/day versus doubling the dose of budesonide to 1600 μg/day. In this subgroup with concomitant allergic rhinitis, the treatment-group difference for change from baseline in morning peak expiratory flow significantly favored addition of montelukast versus doubling the dose of inhaled budesonide (difference = 14.2L/min, p = 0.03); this treatment difference was not significant (4.2 L/min, p = 0.18) in the complete study cohort11- 41. Another recent study has shown a dual utility of cysteinyl leukotriene antagonism for simultaneous treatment of asthma and allergic rhinitis. Studied in a well-characterized challenge model of patients exposed to airborne cat allergen, patients on montelukast were approximately twice as likely to be protected from a simultaneous lower- and upper-airway reaction to airborne cat allergen when taking montelukast, compared with placebo42.

Because montelukast has demonstrated consistent and significant efficacy in studies of asthma, the current study (primarily designed as a rhinitis study) was not specifically designed to assess asthma efficacy. Nonetheless, efficacy in the asthma endpoints that were measured in this 2-week study - global evaluations of asthma and use of short-acting -agonists - provides an internal validation of the treatment effect of montelukast on asthma and supports the ability of montelukast, as a single oral tablet, to treat both diseases simultaneously. Future studies could be designed explicitly to assess the efficacy of montelukast for improving symptoms of rhinitis simultaneous with improving objective measures of asthma.

In conclusion, our results demonstrate that montelukast, with a tolerability profile similar to that of placebo, provides relief from symptoms of seasonal allergic rhinitis in patients who have active asthma, possibly by addressing the underlying systemic inflammation in the two conditions. This paper also indicates that cysteinyl leukotriene antagonism, earlier shown to be beneficial for the treatment of asthma and allergic rhinitis as distinct conditions, also has therapeutic utility in patients with both conditions concomitantly. By relieving symptoms of allergic rhinitis in patients with asthma, montelukast offers physicians an option that may reduce overall therapy needed for these two linked conditions while providing overall clinical benefit.

Acknowledgment

We thank Ms. Gail Larkins for her assistance in managing the performance of this study.

Supported by a grant from Merck Research Laboratories, Rahway, NJ, USA.

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Paper CMRO-2682, Accepted for publication: 23 July 2004

Published Online: 20 September 2004

doi: 10.1185/030079904X3348

George Philip1, Anjuli S. Nayak2, William E. Berger3, Francisque Leynadier4, France Vrijens1, S. Balachandra Dass1 and Theodore F. Reiss1

1 Merck Research Laboratories, Rahway, NJ, USA

2 University of Illinois, Peoria, IL, USA

3 Southem California Research, Mission Viejo, CA, USA

4 University Paris, Paris, France

Address for correspondence: Dr George Philip, Merck Research Laboratories, Respiratory & Allergy Department, Mail code RY34B- 344, 126 East Lincoln Avenue, Rahway, NJ 07065, USA

Copyright Librapharm Oct 2004

Source: Current Medical Research and Opinion

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