Published ahead of print on November 12, 2004, doi:10.1164/rccm.200407-894OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200407-894OC
Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent AsthmaDanish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark; Department of Pediatrics, JW Goethe University Children's Hospital, Frankfurt, Germany; Pediatric Pneumology and Allergy, Hospital Severo Ochoa, Leganes, Madrid, Spain; Department of Respiratory Medicine, National Heart and Lung Institute & Wright Fleming Institute of Infection & Immunity, Imperial College London, United Kingdom; and Merck and Co., Inc., Whitehouse Station and Rahway, New Jersey Correspondence and requests for reprints should be addressed to Hans Bisgaard, M.D., Professor of Pediatrics, Department of Pediatrics, Copenhagen University Hospital, DK-2920 Gentofte, Copenhagen, Denmark. Email: Bisgaard{at}copsac.dk
The PREVIA study was designed to investigate the role of montelukast, a leukotriene receptor antagonist, in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms. The study was a 12-month multicenter, double-blind, parallel-group study of patients with asthma exacerbations associated with respiratory infections and minimal symptoms between episodes. Patients were randomized to receive oral montelukast 4 or 5 mg (depending on age) (n = 278) or placebo (n = 271) once per day for 12 months. Caregivers recorded children's symptoms, ß-agonist use, and health care resource use in a diary card. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2.34 episodes on placebo. Montelukast also delayed the median time to first exacerbation by approximately 2 months (p = 0.024), and the rate of inhaled corticosteroid courses (p = 0.027) compared with placebo. Montelukast effectively reduced asthma exacerbations in 2- to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated.
Key Words: controlled clinical trial • leukotriene receptor antagonist • pediatric Asthma generally begins and has its greatest prevalence in children younger than 5 years old (1–3). This age group often presents with intermittent symptoms (i.e., long asymptomatic periods interrupted by episodes of asthma generally in association with the common cold). The episodic nature of this type of asthma may be due to greater variability of asthma in young children, underreporting of symptoms because of reliance on second-hand caregiver report, increased susceptibility of respiratory infections, or decreased effectiveness of current controller treatment in the younger age group. Predicting an asthma exacerbation in children younger than 5 years old is difficult because objective measurements are not generally available and documenting the episodes relies on second-hand caregiver reports. Although daily symptoms are rare, asthma exacerbations are more common in preschool individuals with asthma compared with school children with asthma irrespective of concurrent controller treatment. Exacerbations exhibit no apparent correlation with prior changes in symptoms or ß-agonist use. Without such predictors, clinicians and caregivers are unable to take acute preventive steps to prevent or prepare for an exacerbation. Effective, well tolerated preventive therapy would therefore appear to be the strategy of choice. Recognition of the importance of inflammation underlying the pathology of asthma has led to the recommendation that controller therapy with inhaled corticosteroids be used in all patients with persistent asthma (4, 5). Although use of systemic corticosteroids may reduce the number of hospitalizations, viral-induced exacerbations have shown disappointing response to corticosteroid treatments, and therapy with maintenance doses of inhaled corticosteroids has not demonstrated any meaningful or consistent clinical benefit in viral-induced asthma (6–8). No preventive therapy has thus far proven worthwhile, and guidelines only recommend therapy with ß-agonists on demand for intermittent asthma (5). Viral infections, predominantly with rhinovirus, account for up to 85% of childhood asthma exacerbations, daily symptoms, and exacerbations in children (9) and adults (10) with asthma. Evidence suggests that leukotrienes play a key role in viral-induced respiratory illness. The leukotriene C4 concentrations in nasopharyngeal secretions of young children with viral-induced wheeze was elevated compared with children who reacted only with upper airway symptoms (11) and can be detected up to 28 days after the onset of viral-induced respiratory illness (12), suggesting the need for long-term treatment. The leukotriene receptor antagonist, montelukast, has proven efficacy in the control of asthma exacerbations in adults (13), school children (14), and preschool children (15) with persistent asthma and in adults with aspirin-intolerant asthma (16). In addition, montelukast significantly reduced symptoms and exacerbations from respiratory syncytial virus postbronchiolitis in infants without asthma (17). The purpose of this study was to investigate the effect of regular montelukast therapy on asthma exacerbations in young children 2 to 5 years old with a history of intermittent asthma associated with the common cold and minimal symptoms between episodes. Some of the results of these studies have been previously reported in the form of an abstract at the American Thoracic Society International Conference (Orlando, FL, 2004) (18) and at the European Respiratory Society Meeting (Glasgow, Scotland, 2004) (19).
Study Design This was a multicenter, double-blind, parallel-group randomized study comparing the clinical effect of once-daily oral montelukast with placebo on the number of asthma exacerbation episodes in 2- to 5-year-old children with intermittent asthma. The study was conducted at 68 sites in 23 countries. Written informed consent approved by the respective institutional review boards or ethical review committees was obtained from parents or legal guardians of each patient. The study consisted of a 1-week screening period; a 2-week, single-blind, placebo run-in period; followed by a 48-week, double-blind active treatment period. After the run-in period, patients were randomly assigned to receive montelukast 4-mg chewable tablet (5-mg chewable tablet if they turned age 6) or image-matching placebo.
Patients
Virologic Testing
Efficacy Endpoints
Statistical Analysis
Patients A total of 768 patients were screened for eligibility, and 549 patients entered the double-blind active treatment period; 278 received montelukast and 271 received placebo. Of these, 265 in the montelukast group and 257 in the placebo group were included in the intention-to-treat analysis (Figure 1). There were no clinically meaningful differences between treatment groups for baseline characteristics (Table 1). The majority of patients (85%) had asthma symptoms no more than twice per week during the month before entry into the study and  67% of patients had not used oral corticosteroids for 1 year before study entry (Table 1). Approximately 45% of patients used inhaled corticosteroids in the 6 months before study entry. The mild nature of asthma between exacerbations is illustrated in Figure 2, which shows total asthma symptoms score for 30 days before and after an exacerbation normalized to the day the exacerbation was reported.
Compliance with the treatment regimen as assessed by tablet count was similar between groups. The average percentage of days in which patients were fully compliant was 98.2% in the montelukast group and 97.9% in the placebo group.
Efficacy
The proportion of patients with asthma episodes (at least three consecutive days with symptoms and a least two treatments of ß-agonist use) was significantly lower in the montelukast group (45%) compared with the placebo group (56%) (p = 0.008). Over the course of the year, only 5% of all patients were hospitalized for asthma: 4.2% in the montelukast group and 5.8% in the placebo group. The proportion of patients with at least one unscheduled visit to a physician for asthma was 37.0% in the montelukast and 42.4% in the placebo group. For patients with at least one exacerbation, the average duration and severity of an exacerbation episode were similar for both treatment groups. The median average duration and severity of an exacerbation episode was similar in the two treatment groups. The percentage of days without asthma was 75.8% in the montelukast group and 72.7% in the placebo group. The least squares mean difference between groups was 3.48% (95% confidence interval, –0.13, 7.08) in favor of montelukast (p = 0.059). Montelukast significantly reduced peripheral blood eosinophils by 4% compared with a 3.7% increase in the placebo group, a difference in medians of 7.7% (p = 0.010). The proportion of patients who missed any time from daycare, playschool, or school, and the proportion of patients whose asthma affected their caregivers were similar in both treatment groups and did not show any trend over time. The risk of having an exacerbation of asthma was significantly greater in the fall and significantly lower in the summer for both treatment groups. Percentage of patients with an exacerbation episode is represented over the calendar year (normalized for hemisphere) for montelukast and placebo in Figure 5. The interaction between treatment and season effects was not significant (p = 0.551), indicating that the treatment effect was consistent throughout the year. When adjusted for season effect, montelukast significantly reduced the hazard of having an exacerbation episode compared with placebo (p = 0.017), corroborating the analysis of time to first exacerbation without season effect.
Virus Identification Eight study centers selected for viral identification randomized 92 patients (46 montelukast, 46 placebo). Demographics of patients at these sites were similar to those of the total patient population (see Table E1 in the online supplement). A total of 158 nasal aspirates were taken; 65 in the montelukast group and 93 in the placebo group (patients may have had more than one aspirate). On average, 1.75 samples per patient per year were taken in the montelukast group and 2.46 in the placebo group, a reduction of 29% (95% confidence interval –3, 51) (p = 0.070), suggesting that caretakers perceived fewer incidents of cold symptoms in patients on montelukast. Eighty-two samples (51.9%) were negative for all virology tests and 76 (48.1%) had at least one test positive. The most common positive tests were for rhinoviruses (27.6%), coronaviruses (9.0%), and respiratory syncytial virus (8.3%) (Table 4).
Fifty-two nasal aspirates were associated with an exacerbation. Virus was identified in 27 of these exacerbations. Because of this small number, treatment effect on exacerbations was not formally analyzed with respect to the presence of virus.
Safety No patients in the montelukast group discontinued therapy because of an adverse experience considered by an investigator to be drug-related. Three patients in the placebo group discontinued therapy because of adverse experiences of abdominal pain, mood swings, or hypersensitivity considered to be drug-related. Three patients in the placebo group discontinued therapy because of asthma.
This study is the first to demonstrate beneficial controller therapy in 2- to 5-year-old patients with mild intermittent asthma. This study showed that once-daily treatment with montelukast significantly reduced asthma exacerbations related to respiratory tract infections compared with placebo over a 12-month period in 2- to 5-year-old patients with intermittent asthma. Montelukast also significantly reduced time to first exacerbation, as well as ß-agonist and inhaled corticosteroid use. After an exacerbation occurred, the severity and duration of an exacerbation was similar in both treatment groups among patients. Montelukast was generally well tolerated; the incidence of drug-related adverse experiences was similar to placebo. The effect was independent of gender, age, race, atopic diathesis, allergy, or baseline eosinophils. In this study, we defined an exacerbation episode as three consecutive days with respiratory symptoms requiring use of rescue medication or hospitalization. A defining feature of asthma is the daily variability of symptoms. The choice of 3 days was made to eliminate the inclusion of random fluctuation of symptoms as an exacerbation episode. This approach assured a consistent interpretation of the signs and symptoms that defined a true exacerbation. Sensitivity analysis using other cutoff levels for number of days, symptoms score, and ß-agonist use showed a similar treatment effect. Viral-induced asthma exacerbations are seasonal, but seem to occur year-round outside the summer (20). Patients had few exacerbations and few or no asthma symptoms during the summer season in both groups for the Northern and Southern hemispheres; however, the treatment effect of montelukast was consistent throughout the rest of the year (Figure 5), suggesting that the treatment effect observed may have related to viral-induced exacerbations. In an exploratory subanalysis within this study, viral identification, associated with symptoms, was performed in a subgroup of patients. The most frequently observed viruses were rhinoviruses followed by coronaviruses and respiratory syncytial virus. Rhinoviruses were the most common type of virus detected in nasal aspirates from children 9 to 11 years old with respiratory symptoms associated with viral infections (9). Slightly less than 50% of aspirates in our study were positive in contrast to approximately 80% positive in the previous study (9). The most likely explanation for this lower detection rate is suboptimal reporting and sampling in the present study compared with the previous one (9), because the present study was a multicenter one and there was no specific expertise in reporting on the children's part, nor in sampling on the investigators' part, whereas the previous study employed children previously trained in documenting and reporting such exacerbations and sampling was performed by highly trained and skilled investigators. It is also possible that some exacerbations were caused by triggers other than viral infections such as allergies. However, as indicated in the subgroup analysis, the treatment effect for patients with or without a history of allergic rhinitis was similar. The distribution of exacerbations episodes over the year was more consistent with viral exacerbations than allergy-related exacerbations. Although some exacerbations could be associated with allergies, the timing of the exacerbations over the year and the consistent effect in patients with and without allergic rhinitis suggest that the majority of exacerbations were likely viral-induced. As an incidental finding in the virus substudy, the number of common colds (criteria for nasal aspirate sampling) was reduced by 29% in the montelukast group (p = 0.07). This observation could be confounded by the treatment effect on exacerbations associated with an upper respiratory infection (e.g., exacerbations may increase the caregiver's attention to the symptoms). The rate of virus identification was similar in the two treatment groups. Future studies should explore if symptoms of common cold may be reduced by montelukast. Recently, metapneumonia virus was detected in 20% of specimens from young children with acute respiratory illnesses for which no cause was previously found (21); however, in the present study, the rate of detection of metapneumovirus was very low (1%, Table 4), suggesting that in this population it was not a major contributor to viral- induced exacerbations. It is possible that some patients had mild persistent asthma rather than intermittent asthma. However, such categories are somewhat arbitrary and children may move in and out of different severity groups (22, 23). The present study is a rigorous attempt to distill a large group of children with intermittent asthma. Patients were included in the study only if they were asymptomatic in the past 3 months and did not use ß-agonists between exacerbation episodes. The inclusion criteria allowed randomization of patients with symptoms up to 4 days in 2 weeks during the run-in period. Up to 15% of patients had symptoms more than 2 times per week and 16% had nocturnal awakenings more than 2 times per month at baseline, which would place them in the mild persistent category according to the Global Initiative for Asthma (GINA) guidelines. However, patients with symptoms greater than 1.0 (average score on four daily daytime symptoms questions, range 0–5) on more than 2 consecutive days, and on more than a total of 4 days during the 2-week placebo run-in period did not qualify for the study. Therefore, most patients probably had intermittent asthma. In addition, no preventive therapy other than montelukast or placebo were allowed during the study and the number of exacerbations and the mean daily symptoms score were low throughout the year (Figure 2). Patients in this clinical trial represent an age group and category of patients with asthma that are seldom studied. Airways inflammation is present in adults with intermittent asthma (24) and in children with mild asthma (25); however, it is not known if very young children with viral-induced intermittent asthma have similar inflammation. It is also not known whether intermittent asthma reflects a persistent mild form of asthma with rare symptoms or a separate entity such as viral-induced reactive airway disease. Consistent with the lack of clinical efficacy seen with inhaled steroid therapy in such patients, asthma guidelines do not provide guidance for preventive treatment. Although symptoms may be mild or absent outside times of exacerbation, asthma exacerbations are troublesome and the consequences of recurrent viral infections and resulting inflammation of the lower airways are unknown. However, a reduction in the number of exacerbation episodes and subsequent inflammation by montelukast in this study may lessen any impact that viral infections have on the course of the illness in addition to symptom relief. Although the results of this study were positive, it is not anticipated that mild intermittent pediatric patients would be treated daily with montelukast. The present findings prove the concept that montelukast reduced exacerbations in intermittent asthma, but it is not the claim of the study that management should necessarily apply year-round regular treatment. Because exacerbations were seasonal, therapy could begin before the viral season when the exacerbation rate is high. Alternately, length and initiation of therapy could be based on severity of symptoms and susceptibility experienced by a patient during exacerbation. Future studies should address the feasibility of beginning treatment at first signs of an upper respiratory infection in susceptible patients. Studies evaluating the use of regular inhaled corticosteroids in children with viral-induced intermittent asthma, similar to the patient characteristics of the present study, showed that neither the rate nor the frequency of wheezing episodes changed with such therapy (6–8). The 32% reduction by montelukast seems clinically relevant and comparable to that seen in patients with asthma of a similar age. Knorr and colleagues treated 2- to 5-year-old patients with asthma with montelukast for 12 weeks (15). Poisson regression analysis of data from the Knorr study demonstrated that montelukast reduced asthma attacks by 24.5% (1.4 asthma attacks/year on montelukast versus 1.8 asthma attacks/year on placebo)—not unlike the reduction in exacerbation episodes in the current study. Asthma attacks (worsening asthma requiring rescue medication or asthma resource use) in the Knorr study (15) and exacerbations in the current study were evaluated similarly; therefore, the reduction is consistent. Montelukast did not significantly alter the duration or severity of an asthma exacerbation after an episode occurred. The study was not designed to specifically investigate the effect of montelukast on these endpoints because patients were treated with other therapies during an asthma exacerbation. The action plan for worsening asthma may have led to some standardization of episode duration (e.g., patients were given corticosteroids routinely for predefined periods even if symptoms resolved earlier). Measurement of severity of an exacerbation episode also included such treatments. Therefore, the effect of montelukast on these endpoints could not be clearly defined in this trial. In conclusion, montelukast significantly decreased the rate of asthma exacerbations and increased time to exacerbation in 2- to 5-year-old patients with asthma whose symptoms were intermittent. Consistent with these findings, the proportion of patients requiring inhaled corticosteroids or ß-agonists were reduced by 30% and 40%, respectively, compared with placebo. This study is the first to demonstrate that exacerbations of mild intermittent asthma can be successfully treated with a controller agent. The results of this study should be confirmed, because they have broad implications for treatment of intermittent asthma in children where other conventional therapies have failed to show any clinical benefit. Principal Investigators: Austria: T. Frischer Brazil: N.A. Filho, P.R.S. Silva Canada: A. Cheema, F. Ducharme, H.L.Y. Kim, B. Lyttle Chile: R.A. Pinto, M. Boza Colombia: O. Baron, G. Aristizabal Costa Rica: M. Soto Croatia: E. Verona, V. Ahel Finland: M. Uhari, E.J. Valovirta Germany: H-G. Bresser, S. Zielen, C.P. Bauer, F. Friedrichs, J. Seidenberg, W. Leupold, W. Ulrich, A. Schuster, A. Von Berg, D. Reinhardt Greece: K. Priftis, F. Saxoni-Papageorgiou, A. Mihalis Hong Kong: T-F. Leung, K-K. Ng Hungary: G. Uhereczky, I. Kovacs, G. Dobra, B. Nagy, K. Gyurkovits, E. Cserhati Israel: L. Bentur, A. Mandelberg, A. Tal, C. Bibi Italy: A. Capristo, A. Boner, L. Capra, A. Fiocchi, G.A. Rossi Mexico: A. Flores Philippines: M. Sumpaico, A. Jiao Portugal: J.M. Lopes Dos Santos, M. Almeida, N. Ferreira Singapore: A.E. Goh Slovenia: V. Macek South Africa: A.I. Manjra, R. Green Spain: A. Nieto-Garcia, J. Perez-Frias, M. Boquete-Paris, J.M. Garde-Garde Switzerland: J.H. Wildhaber, H. Oswald Taiwan: J-L. Huang, K. Yang, S-D. Shyur, J-Y. Wang
The authors acknowledge the contributions of Theodore F. Reiss, M.D., Barbara Knorr, M.D., and Nancy Santanello, M.D., to the study design, critical review of the data, and review of the manuscript (Dr. Reiss); Patricia Brady and Pam S. Dellea for coordination of the study; Veerle Coenen for coordination of study data, Isabel Boaventura, M.D., for protocol development; and Tatiana Kebadze for carrying out the virus detection assays. They also acknowledge the excellent study monitors, investigators, and patients.
Supported by Merck and Co., Inc. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: H.B. has, within the last 3 years, received honoraria for lectures and attendance at pediatric Advisory Boards for Aerocrine, AstraZeneca (AZ), GlaxoSmithKline (GSK), Hoffman-La-Roche, Merck Sharpe and Dohme (MSD), Novartis, and Yamanouchi and owns world patents in the pharmaceutical industry in the respiratory field but receives no royalty. The Danish Pediatric Asthma Center has, in the last 3 years, received research grants from the following industry partners in increasing order: Aerocrine, MSD, GSK, and AZ; S.Z. received 5,200 Euros in 2004 for serving on an Advisory Board for MSD and has participated as a speaker in scientific meetings financed by MSD and, in 2003, received a research grant from MSD of 25,000 Euros; M.L.G.-G. is an employee of Merck & Company and holds stock options; S.L.J. has received grants to investigate mechanisms of the virus induced asthma from Merck ($200,000) and GSK ($1 million); L.G. is an employee of Merck & Company and holds stock options; J.M. is an employee of Merck & Company and holds stock options; C.A.T. is an employee of Merck & Company and holds stock options; P.P. is an employee of Merck & Company and holds stock options. Received in original form July 12, 2004; accepted in final form November 5, 2004
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ABSTRACT
METHODS
0.001) reduced asthma exacerbation episodes, the primary efficacy endpoint of the 12-month study compared with placebo (
