Montelukast vs. Inhaled Low-Dose Budesonide as Monotherapy in the Treatment of Mild Persistent Asthma: A Randomized Double Blind Controlled Trial

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1 Montelukast vs. Inhaled Low-Dose Budesonide as Monotherapy in the Treatment of Mild Persistent Asthma: A Randomized Double Blind Controlled Trial by Vikram Kumar, a P. Ramesh, a Rakesh Lodha, a R. M. Pandey, b and S. K. Kabra a Departments of a Pediatrics and b Department of Biostatistics, AIIMS, Ansari Nagar, New Delhi Summary Background: Guidelines recommend daily controller therapy for mild persistent asthma. Montelukast has demonstrated consistent benefit in controlling symptoms of asthma and may be an alternative, orally administered, nonsteroidal agent for treating mild asthma. Aim: To determine whether montelukast is as effective as budesonide in controlling mild persistent asthma as determined by FEV 1. Methods: Between November 2003 to October 2005, participants aged 5 15 years with recently diagnosed mild persistent asthma (n ¼ 62) were randomized to oral montelukast (5 mg daily) [N 1 ¼ 30] or inhaled budesonide (400 kg per day in two doses) [N 2 ¼ 32] in a single center, double-blind study. Results: Baseline demographic and spirometric parameters were comparable. The median (95% confidence interval) percentage predicted FEV 1 was similar in the two groups after 12 weeks of treatment (budesonide: ( %), montelukast: 75 ( )%; p ¼ 0.44). There was similar improvement in spirometric parameters and clinical symptom scores in both the groups. There was no statistically significant difference between the groups in the need for rescue drugs as well as side effects reported by parents. Conclusion: Montelukast is as effective as inhaled budesonide in the treatment of mild persistent asthma in children aged 5 15 years. Montelukast may be used as an alternative to low dose inhaled corticosteroids for management of mild persistent asthma. Key words: mild persistent asthma, montelukast, budesonide. Introduction Asthma is the most common chronic illness of childhood in developed as well as developing countries. [1 3] The basic pathophysiology of asthma consist of chronic inflammation of airways. Cysteinyl leukotrienes are inflammatory bioactive lipids produced by various cells. They are present in increased amounts in airway secretions of all different asthma phenotypes and can induce all the inflammatory changes observed in the airways of asthmatic patients. For this reason, an attempt to inhibit the actions of these mediators through the use of cysteinyl receptor antagonists appears rational [4]. Montelukast (MK-0476) is an orally administered potent, specific antagonist of leukotriene receptors [5, 6] that is approved for use in asthma. In adult studies, montelukast (10 mg once daily at bedtime) demonstrated improvement in parameters of asthma control, including forced expiratory volume in 1 s (FEV 1 ), daytime and night-time symptom scores, and as-needed b-agonist use [7, 8]. However, there is limited literature on comparison of montelukast and inhaled corticosteroids (ICS) in mild persistent asthma in children [9 11]. Therefore we compared efficacy of montelukast and ICS in management of mild persistent asthma in children between 5 and 15 years age. Methods This randomized double blind controlled trial was carried out in Pediatric Chest Clinic of All India Institute of Medical Sciences, a tertiary care hospital in New Delhi, India between November 2003 and October Correspondence: Dr S. K. Kabra, Additional Professor, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi <skkabra@hotmail.com>. Participants Children between the ages of 5 and 15 years of either sex with recently diagnosed mild persistent asthma were subjects of the study. Mild persistent asthma ß The Author [2007]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 325 doi: /tropej/fmm038

2 was defined as asthma symptoms occurring more than two times in a week but <1 episode per day and exacerbation may affect activity, night time symptoms more than two times a month and peak expiratory flow rate (PEFR) more than or equal to 80% of the predicted [1]. Children with any other chronic illness like tuberculosis, cystic fibrosis; children unable to use inhaler with spacer/to perform spirometry were excluded. Intervention. Patients were randomized to receive either budesonide metered dose inhaler (MDI) (400 mg per day in two doses) þ placebo tablets or montelukast tablets þ placebo MDI. Other supportive care was continued as per standard guideline [1]. Evaluation. Detailed demographic profile and baseline investigations of the subjects were obtained. Spirometry was done using a portable Spiro meter (Cosmed Pony) after properly explaining the correct method to the subjects. The best of three spirometry attempts was recorded. The absolute and percentage predicted values of PEFR, FEV 1, FVC, FEF-25, FEF-50 and FEF-75 were recorded. After recording these parameters, patients were given the drugs for next 1 month, which included one MDI and one pack of 30 tablets. Spacers were used for delivery of drug/ placebo from the MDI. Parents were explained to maintain daily symptom diary, need for rescue drug, any adverse side effects and visit to emergency or local practitioner. Children were followed up every 4 weeks for 12 weeks. Physical examination and spirometry was repeated on each follow-up visit and recorded in a performa. Laboratory tests (hematology, radiology) were obtained at the pre-study visit. Objectives The study was conducted to compare the efficacy of montelukast and ICS in management of mild persistent asthma in children between 5 and 15 years of age. Outcome variables. The change in FEV 1 was the pre-specified primary end point. The change in percentage FEV 1 was compared between the two groups. Other pre-specified end points were mean symptom score for cough, wheezing and sneezing; need for rescue drug with details of drug dosage and duration; symptom free days and side effects. Sample size. A convenient sample size of 60 patients was decided, 30 in each group, as at the time of initiation of this study, there were no similar pediatric studies published. Randomization and blinding. Randomization was done by computer generated simple randomization. For purpose of blinding, similar looking MDIs of budesonide (200 mg per actuation) or placebo and tablets of montelukast (5 mg) or placebo were used. Packets of drugs for each patient were labeled according to randomization sequence by a person not involved in initial or subsequent assessment of the patients. Statistical methods Categorical variables were summarized by frequency (%). Pearson chi-square test was used to compare proportions between the two treatment groups. Comparison of the two groups at baseline and thereafter at each follow-up visit was done. Comparison of various parameters at each follow-up visit with values at the baseline within each group was also done. Continuous variables were summarized by median and 95% confidence intervals. Mann Whitney (Wilcoxon ranksum) test was used to evaluate the differences between the groups. Wilcoxon signed-rank test was used for evaluating the differences in various continuous variables at different times. STATA 7.0 software was used for analysis. Safety and ethical issues Written permission was taken from Drug Controller General of India (DCGI) to conduct the study. The study protocol was approved by the Ethics Committee of AIIMS. A written informed consent was obtained from the parents/legal guardians of study participants. Results From November 2003 to October 2005, 62 children of either sex between the ages of 5 15 years with mild persistent asthma were enrolled in the study. Thirtytwo patients were randomized to receive budesonide (400 mg per day in two doses) from an MDI and placebo tablets. Thirty patients were randomized to receive montelukast tablets and placebo MDI. Four children were lost to follow up, three from montelukast group and one from budesonide group. Two patients, one from each group, were taken out of the study as they had developed skin rashes after few days of starting therapy (Fig. 1). The two groups were comparable in their baseline characteristics except for age and height (Table 1). There was no statistically significant difference in the treatment received in the form of oral bronchodilators, inhaled bronchodilators and theophylline. It was noted that four patients in montelukast group were on ICS for a period of less than 1 week prior to the enrollment in the study and there were none in the budesonide group. The groups were comparable in the baseline spirometric parameters except for FEV 1 and FEF- 75. The mean FEV 1 in group A was 1.4 l and in group 326 Journal of Tropical Pediatrics Vol. 53, No. 5

3 New patients with asthma attended Pediatric chest clinic during study period 760 Mild persistent asthma: 80 Patients enrolled: 62 Moderate persistent asthma Severe persistent asthma Already on inhaled steroids: 12 Staying far off (not possible to follow up): 6 FIG. 1. Trial profile. 1: lost to follow up 1: withdrawn because of rashes Group A Budesonide: 32 B was 1.13 l (95% CI ¼ ) (p ¼ 0.03). It persisted at second follow-up visit at 2 months (p ¼ 0.006). However, there was no statistical difference of change in FEV 1 from baseline to the end of the study in either group (Table 2). On comparing the change in percentage predicted FEV 1 from baseline to end of study within the groups, there was improvement in both the groups but it was not statistically significant. There was also no statistically significant difference in percentage Group B Budesonide: 30 3: lost to follow up 1: withdrawn because of rashes Total completed: 30 Total completed: 26 TABLE 1 Comparison of baseline parameters Budesonide group (n ¼ 32) Montelukast group (n ¼ 30) p-value Age (year) (mean SD) c Sex (M/F) 25/7 25/ b Cough b Wheeze b Sneezing b Weight (kg) (median) a Height (cm) (median) a Hb (g dl 1 ) 9.9 ( ) 10.1( ) 0.31 a Eosinophils (%) 1 (0 2) 2 (0 3) 0.68 a PEFR (l s 1 ) 2.84 ( ) 2.34 ( ) 0.47 a FEV-1 (l) 1.4 ( ) 1.13 ( ) 0.03 a FEV 1 (% predicted) 76 ( ) 73.5 ( ) 0.64 a FEF-25 (l s 1 ) 2.44 ( ) 1.99 ( ) 0.23 a FEF-50 (l s 1 ) 2.09 ( ) 1.48 ( ) 0.16 a FEF-75 (l s 1 ) 1.45 ( ) 1.26 ( ) 0.70 a FVC (l) 1.55 ( ) 1.24 ( ) 0.08 a a Mann Whitney test; b chi-square; c t-test. Values for spirometric parameters are median (95% CI). predicted FEV 1 between the two groups at the end of the study (Fig. 2). PEFR. On comparing the absolute values of PEFR in the two groups there was an improvement in values: 2.84 l s 1 (95% CI ¼ ) at baseline to 3.04 l s 1 (95% CI ¼ ) at end of study in children getting budesonide and from 2.34 l s 1 (95% CI ¼ ) to 2.74 l s 1 (95% CI ¼ ) in children getting montelukast. Journal of Tropical Pediatrics Vol. 53, No

4 TABLE 2 Changes in FEV 1 on follow up Budesonide group Montelukast group p-value a FEV 1 (L) baseline 1.4 ( ) (n ¼ 32) 1.13 ( ) (n ¼ 30) 0.03 FEV 1 (L) at 1 month 1.39 ( ) p ¼ 0.56 b (n ¼ 30) 1.11 ( ) p b ¼0.76 (n ¼ 26) 0.07 FEV 1 (L) at 2 months 1.48 ( ) p ¼ 0.11 b (n ¼ 30) 1.18 ( ) p ¼ 0.98 b (n ¼ 26) FEV 1 (L) at 3 months 1.44 ( ) p ¼ 0.17 b (n ¼ 30) 1.26 ( ) p ¼ 0.30 b (n ¼ 26) 0.08 Percentage a Comparing the values between montelukast and budesonide groups (Mann whitney test). b Comparing the values within the same group with the baseline value (Wilcoxan signed rank test). Values are median (95% CI) Baseline 1 month 2 months 3 months Changes in FEV 1 (percentage predicted) Budesonide group Montelukast group FIG. 2. Changes in FEV 1 (percentage predicted) on follow up. There was no statistical difference in the change of FVC, percentage predicted FVC, change of FEF-25, percentage predicted FEF-25, FEF-50 and percentage predicted FEF-50 from base line to end of study within the two groups and between the two groups. Trend towards improvement was observed in both the groups. Secondary outcome variables There was no statistically significant difference in the average symptom score and symptom free days for cough, wheeze, sneezing in either group from the baseline to the end of the study. Two children in the budesonide group required inhaled salbutamol for cumulative of 24 days; four children in the montelukast group required inhaled salbutamol for cumulative of 30 days. These differences were not statistically significant. None required any oral steroids. Two patients, one in each group had developed skin rashes. Two patients in budesonide group reported sedation. There was no other side effect reported during the study in either group. Discussion This study suggests that montelukast and low-dose inhaled budesonide are comparable in the treatment of mild persistent asthma in children between 5 and 15 years of age over a period of 3 months. The baseline parameters were comparable in two groups except difference in age and height. The influences of these differences on the differences in the spirometric parameters were taken care of by comparing the percentage predicted values for the spirometric parameters between the two groups. Most of the studies in published literature on montelukast in childhood asthma had compared montelukast with placebo and found that oral montelukast (4 mg chewable tablet) administered once daily is effective therapy for asthma in children aged 2 5 years and is generally well-tolerated without clinically important adverse effects [12, 13]. Similarly, in adults and children aged 6 14 years, montelukast improved multiple parameters of asthma control, and was also effective in reducing markers of chronic inflammation [14, 15]. Studies comparing montelukast and ICS reported conflicting results. A recently published multicenter 12-month noninferiority trial [16] compared montelukast with inhaled fluticasone to assess the increase in the percentage of RFDs (rescue-free days) among 996 children between 6 and 14 years of age with mild persistent asthma. The difference in RFDs between montelukast and fluticasone was <1 day per month. Secondary end points, including percentage of predicted forced expiratory volume in 1 s value, days with ß-receptor agonist use and quality of life, improved in both groups but were significantly better in the fluticasone treatment group. However, patient and parent satisfaction, convenience and adherence to treatment were better with montelukast than ICS. In a similar 12-month parallel-group multicenter study [17] looking at RFDs as a composite clinical marker of the efficacy of control of mild persistent asthma in participants aged years with mild persistent asthma, oral montelukast (10 mg once nightly) was comparable to inhaled fluticasone (88 mg twice daily) Ostrom et al. [18] reported superiority of fluticosone over montelukast in their randomized, double-blind, 12-week study on 342 children 328 Journal of Tropical Pediatrics Vol. 53, No. 5

5 (6 12 years of age) in improvement in FEV 1, PEFR, and percent rescue-free days, night-time symptom scores and mean salbutamol use. Adverse events (69% vs. 71%) were similar. Parents and physicians were more satisfied with fluticasone treatment than with montelukast. The contradictory results of these studies may be because of differences in the patient populations and duration of study. However, in both the studies, the ICS group had better improvement in the spirometric parameters. In our study we found that montelukast was as effective as ICS in improving lung function end points such as peak flow and forced expiratory volume in 1 s (FEV 1 ). The results of our study are also similar to results from a 6-month, open-label trial comparing montelukast with beclomethasone among 6 11 year-old children by Becker et al. [19]. In this study, montelukast and beclomethasone provided equivalent protection with respect to asthmarelated resource utilization, as well as other clinical end points. Knorr et al. [20] found that montelukast demonstrated a consistent effect regardless of concomitant use of inhaled/nebulized corticosteroid or cromolyn therapy. Both montelukast and budesonide were generally well-tolerated. Drug-related adverse experiences occurred in <5% of patients in both the montelukast and budesonide groups; the most commonly reported experiences were skin rash and sedation. This result was comparable with two recent studies. Knorr et al. [20] had concluded that montelukast was welltolerated and efficacious in children with mild persistent asthma. Another study conducted by Van et al. [21] concluded that montelukast was safe over a period of 6 weeks. The major limitation of the present study included small sample size and follow up was for only 3 months. It would have been desirable to have a runin drug-free period of about 2 4 weeks to evaluate the symptom scores and symptom free days. In summary, this study demonstrated that montelukast once daily is as effective a therapy as low dose ICS in 5 15-year-old patients with mild persistent asthma. Montelukast was welltolerated and demonstrated a safety profile similar to ICS. References 1. National Asthma Education and Prevention Program. Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma: NHLBI Workshop Report. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, Ducharame FM, Davis GM. Randomized controlled trial of ipratropium bromide and frequent low doses of salbutamol in management of asthma. J Pediatrics 1998;133: Gergen PJ, Weiss KB. Changing patterns of asthma hospitalization among children: 1979 to JAMA 1990;264: Capristo C, Rigotti E, Boner AL. Update on the use of montelukast in pediatric asthma. 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6 17. Zeiger RS, Bird SR, Kaplan MS, et al. Short-term and long-term asthma control in patients with mild persistent asthma receiving montelukast or fluticasone: a randomized controlled trial. Am J Med 2005;118: Ostrom NK, Decotiis BA, Lincourt WR, et al. Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma. J Pediatr 2005;147: Becker A, Swern A, Tozzi CA, et al. Montelukast in asthmatic patients 6 years-14 years old with an FEV1 > 75%. Curr Med Res Opin 2004; Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998;279: van Adelsberg J, Moy J, Wei LX, et al. Safety, tolerability, and exploratory efficacy of montelukast in 6 to 24 month-old patients with asthma. Curr Med Res Opin 2005;21: Journal of Tropical Pediatrics Vol. 53, No. 5