Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma

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1 Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma Anna A. P. H. Vaessen-Verberne 1, Norbert J. van den Berg 2, Jan C. van Nierop 3, Hein J. L. Brackel 4, Gerardus P. J. M. Gerrits 5, Wim C. J. Hop 6, and Eric J. Duiverman 7, on behalf of the COMBO Study Group* 1 Department of Pediatrics, Amphia Hospital, Breda, the Netherlands; 2 Department of Pediatrics, Flevo Hospital, Almere, the Netherlands; 3 Department of Pediatric Respiratory Diseases, Academic Medical Center/Emma s Children s Hospital, Amsterdam, the Netherlands; 4 Department of Pediatrics, Catharina Hospital, Eindhoven, the Netherlands; 5 Department of Pediatrics, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands; 6 Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands; 7 Department of Pediatric Respiratory Diseases, University Medical Center Groningen/Beatrix Children s Hospital, Groningen, the Netherlands Rationale: For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids, evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids. Objective: To evaluate whether salmeterol/fluticasone propionate (SFP), 50/100 mg twice a day, is noninferior regarding symptom control compared with fluticasone propionate (FP), 200 mg twice a day Diskus in children with symptomatic asthma. Methods: A multicenter, randomized, parallel-group, double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function. Measurements and Main Results: A total of 158 children, 6 16 years old, still symptomatic on FP, 100 mg twice a day, during a 4-week runin period, were included. Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups (per protocol analysis: adjusted mean difference [FP minus SFP] 2.6%; 95% confidence interval, 28.1 to 13.4). Both groups showed substantial improvements of about 25 percent points in symptom-free days (both P, from baseline). Lung function measurements (FEV 1, FVC, PEF rate, and maximal expiratory flow) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week. No differences were found between FP and SFP regarding exacerbation rates, adverse events, or growth. Conclusions: In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid. Clinical trial registered with (NCT ). Keywords: asthma; child; inhaled corticosteroid; long-acting b 2 -agonist Asthma is the most common chronic disease in children. Recent guidelines focus on the control status of asthma, aiming to control symptoms and prevent exacerbations, and allowing the child to have a normal lifestyle, including normal physical activity (1, 2). Inhaled corticosteroids are the mainstay of asthma treatment and are presently recommended for children (Received in original form February 8, 2010; accepted in final form July 8, 2010) * A complete list of members may be found before the beginning of the REFERENCES. Supported by an unconditional grant from GlaxoSmithKline Pharma Europe. Correspondence and requests for reprints should be addressed to Anna A.P.H. Vaessen-Verberne, M.D., Ph.D., Department of Pediatrics, Amphia Hospital, Langendijk 75, 4819 EV Breda, the Netherlands. avaessen-verberne@ amphia.nl This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 182. pp , 2010 Originally Published in Press as DOI: /rccm OC on July 9, 2010 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject In children with asthma, addition of long-acting bronchodilators to moderate doses of inhaled corticosteroid has not been shown superior to doubling the doses of inhaled corticosteroid, so the place of long-acting bronchodilators in stepwise treatment plans is less clear than in adults. What This Study Adds to the Field The efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid. Combination of a longacting bronchodilator with inhaled corticosteroid therefore is a good alternative in step 3 of treatment plans. with persistent mild, moderate, and severe asthma in national and international guidelines (1, 3). There is substantial evidence in pediatric studies that inhaled corticosteroids improve daytime and nighttime symptoms (4, 5), reduce exercise-induced bronchoconstriction (6), reduce the number of asthma exacerbations (4, 5), and reduce bronchial hyperresponsiveness (5). Several international pediatric guidelines now advocate adding a long-acting bronchodilator instead of doubling the dose of the inhaled corticosteroid in the stepwise treatment approach for those children who remain symptomatic on low doses of inhaled corticosteroids (7). However, the dose step at which long-acting bronchodilators should be added differs between guidelines from low dose (8) to moderate doses of inhaled corticosteroids (1, 2). Few studies in children have focused on the direct comparison of adding a long-acting bronchodilator with increasing the dose of inhaled corticosteroids (9). In contrast to the data in adult studies none of these studies shows a superior effect on asthma control parameters of adding a long-acting bronchodilator. Although inhaled corticosteroids do not seem to affect final adult height, inhaled corticosteroids have shown dose-dependent growth reduction in 1-year studies, and shortterm growth effects as measured by knemometry (10). For parents and clinicians this still is a point of concern. Therefore, asthma control in children should preferably be obtained with the lowest possible dose of inhaled corticosteroid. We hypothesize that adding a long-acting b 2 -agonist to a moderate dose of inhaled corticosteroid is noninferior to doubling the dose of inhaled corticosteroids in terms of symptom control and lung function parameters.

2 1222 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL METHODS We performed a multicenter, randomized, parallel-group, double-blind study in children aged 6 16 years still symptomatic on conventional doses of inhaled corticosteroid, comparing the addition of a long-acting b 2 -agonist with doubling the dose of inhaled corticosteroid. The trial, GSK study number SAM101667, was a registered clinical trial. Patients From June 2005 to October 2008, 257 children were enrolled in the study. The study was approved by the medical ethical committees of the participating centers. Written informed consent was given by parents and children 12 years and older. All children had moderate asthma; a history of bronchial hyperresponsiveness; and used inhaled corticosteroids (maximum 250 mg fluticasone or equivalent). Study Design All children enrolled in the study used fluticasone propionate (FP) dry powder, 100 mg twice a day by Diskus inhaler, during the 4-week run-in period. Salbutamol, 200 mg Diskus, was allowed for symptom relief during run-in and study period. The run-in period was scheduled to select those children still symptomatic despite regular use of FP, 100 mg twice a day. Children were considered symptomatic when they had a cumulative symptom score of greater than or equal to 14 for the last 14 days of the run-in period. Symptoms were separately scored for cough, wheeze, and shortness of breath, with a daily maximum score of 18 (see Figure E1 in the online supplement). Symptomatic children were randomized to either FP, 200 mg twice a day Diskus (FP group), or salmeterol/fp, 50/100 twice a day Diskus (SFP group), for 26 weeks. Children were evaluated at clinical visits during the treatment phase at 1, 6, 16, and 26 weeks. Primary outcome parameter was the percentage of symptom-free days during the last 10 weeks of the treatment period. Measurements Lung function measurements (FEV 1,FVC,FEV 1 /FVC, maximal expiratory flow [MEF 50 ], and PEF rate) were recorded at the start of the run-in period, at randomization, and at all visits during the 26-week treatment phase. PD 20 methacholine and exhaled nitric oxide (FeNO, in selected centers) were assessed at the start and the end of the treatment period. Lung function was measured according to American Thoracic Society/European Respiratory Society recommendations (11). Reference values of Zapletal and coworkers were used (12). Methacholine provocation tests were performed using a dosimeter method, as described previously (13). FeNO measurements were performed according to European Respiratory Society recommendations (14). Diary records were kept throughout the study period. Information on exacerbations was recorded at each visit. Mild exacerbations were defined as additional visits to a physician for increase in symptoms. An exacerbation was graded as a moderate exacerbation in case a course of prednisolone was prescribed at the discretion of the physician. In case of an emergency department visit or hospitalization, the exacerbation was considered as severe. Height was recorded using a stadiometer at the start of the run-in period, and at the start and at the end of the treatment period. Statistical Analysis The study was designed as a noninferiority study, and aimed at excluding a difference in favor of the FP arm of 15% or greater regarding the mean percentage of symptom-free days during the last 10 weeks of the treatment period. Power calculations based on data of a similar group of patients had shown that, for a power of 80%, 76 patients were required in each group (15). Categorical and continuous data were compared between groups using the chi-square/fisher exact test or the Mann-Whitney test, respectively. The mean values of percentages of symptom-free days, lung function data, logfeno, and logpd 20 were compared using repeated measurements analysis of variance (SAS PROC MIXED), with adjustment for the run-in baseline value, sex, age, and center. Comparison of exacerbation rates was done using the Kaplan-Meier methodology and the log-rank test. All analyses were prespecified and were done in duplicate for the intention-to-treat population and for the per-protocol population. For additional information on study design, measurements, and statistical analysis, see online supplement. RESULTS Of 257 children evaluated for participation, 158 children were randomized (134 after the standard run-in period, 24 after an extended run-in period). The major reason for not being included in the study was lack of symptoms during the run-in period (Figure 1). Baseline characteristics are listed in Table 1. At randomization treatment groups were similar regarding the distribution of age, sex, use of asthma medication, asthma symptoms, and lung function parameters. During the treatment phase seven children dropped out, one in the FP group and six in the SFP group. The dropout rate did not significantly differ between the treatment groups (P ; Fisher exact test). The number of patients evaluated in the per-protocol analysis was 63 and 62 for the FP and SFP arm, respectively (Figure 1). Compliance with study medication was 92% and 87% for the FP and SFP groups, respectively. Asthma Symptoms and Exacerbations The percentage of symptom-free days did not differ between treatment groups in any of the treatment periods (0 6, 6 16, and weeks) (Figure 2). The mean adjusted difference in symptom-free days between the FP and SFP group during the last 10 weeks was 2.6% (95% confidence interval [CI], 28.1 to 13.4; P ) in the per-protocol analysis and 0.4% (95% CI, 29.1 to 9.9; P ) in the intention-to-treat analysis. Because all per-protocol and intention-to-treat analyses showed similar findings, further results are only reported for the intention-totreat population. Within each treatment group the percentage of symptom-free days increased from baseline to the last 10 weeks of treatment by about 25 percent points (both P, 0.001). In the FP group the mean percentage of days on which rescue salbutamol was used gradually decreased from 35% during the run-in period to 20% at the end of treatment. The corresponding percentages in the SFP group were 38% and 22%, respectively, with no significant difference of the mean changes from baseline between treatment groups (P ) (see Figure E2). Twenty-two patients had one or more asthma exacerbations during the study period, 9 in the FP group and 13 patients in the SFP group. In the FP group four patients (5%; 95% CI, 1 12%) had moderate or severe exacerbations compared with eight patients (10%; 95% CI, 5 19%) in the SFP group (difference 5%; 95% CI, 23 to 14%; P ). Both severe exacerbations were in the SFP group. A combined ranked assessment of all exacerbations (mild, moderate, and severe) did not show a significant difference between treatment groups (see Table E1). Kaplan-Meier curves for time until the first exacerbation and for time until a moderate or severe exacerbation did not show significant differences between treatment groups (see Figure E3). Lung Function Parameters Measurements of FEV 1, FVC, FEV 1 /FVC, MEF 50, and PEF rate did not differ significantly between groups during the whole treatment period (Table 2), except for a slight advantage in MEF 50 in the SFP group at 1 week. No significant changes occurred from baseline. Regarding airway responsiveness at the end of treatment, although PD 20 methacholine improved from baseline in both treatment groups with 0.8 (P for the significance of change) and 2.2 (P ) doubling dose for the FP and SFP, respectively, the mean changes from baseline did not significantly differ between treatment arms (Table 2). FeNO was measured in 62 patients (33 FP and 29 SFP groups)

3 Vaessen-Verberne, van den Berg, van Nierop, et al.: Doubling Dose of Inhaled Corticosteroid or Addition of Salmeterol 1223 Figure 1. Enrollment of children in the study. FP 5 fluticasone propionate, 200 mg twice a day; SFP 5 salmeterol, 50 mg, and fluticasone propionate, 100 mg, twice a day. Numbers in parentheses denote the number of weeks after randomization at withdrawal. at baseline and in 58 patients after 26 weeks (31 FP and 27 SFP groups). No significant difference between treatment groups was found (Table 2). For each treatment the within groups change from baseline was also not significant (both P. 0.09). Subgroup analyses for the primary end point (percentage of symptom-free days from weeks) were done according to baseline FEV 1 (below versus above median value) and baseline value of FeNO (below versus above median). The median value of FEV 1 was 100% predicted, and the median value of FeNO was 11.5 ppb. No differences in the treatment effects regarding percentage of symptom-free days were found between subgroups based on FEV 1 or based on FeNO (Table 3). TABLE 1. BASELINE CHARACTERISTICS Fluticasone Propionate (n 5 80) Salmeterol/Fluticasone Propionate (n 5 78) Sex Male 49 (61) 42 (54) Female 31 (39) 36 (46) Age, yr 9.3 (1.9) 9.4 (1.8) Race White Asian 2 1 Black 1 3 Mixed 4 4 Asthma duration, yr 5.5 (3) 5.7 (3.1) Atopy* 58 (73) 60 (77) Inhaled corticosteroid duration, yr 4.1 (3) 4.2 (3.1) Oral steroid courses/patient/year 0.10 (0.18) 0.16 (0.43) Oral steroid courses previous year Hospitalizations previous year % Symptom-free days diary card 15 (0 90) 13 (0 90) Daily symptom score diary card 2.5 ( ) 2.3 ( ) FEV 1, % pred (13.9) 99.4 (15.1) PD 20 (mg methacholine) 107 (0.9 to.1570) 55 (3.9 to.1570) Exhaled nitric oxide, ppb 12.8 ( ) 11 (3 106) Data given are numbers (%) of patients, mean (SD), or median (range). * Atopy is defined as specific IgE or positive skin prick test to one or more inhaled allergens. Based on last 14 d of run-in period. Upper limit of testing (highest dose: 1,570 mg).

4 1224 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 2. Percentage symptom-free days from diary at run-in and during treatment. Solid and open symbols represent the fluticasone propionate and salmeterol/ fluticasone propionate treatment groups, respectively. Squares and circles denote the intention-to-treat and per-protocol populations, respectively. Data shown are SE from analysis of variance. Statural Growth The FP and SFP groups did not differ for growth: mean statural growth for both groups was 2.9 cm in the 26-week period. Baseline adjusted difference between the FP and SFP groups of the change from baseline in height standard deviation score was (95% CI, to 0.04; P ). Adverse Events One hundred twenty-one children reported at least one adverse event, 62 and 59 children, respectively, in the FP and SFP groups (P ). The most frequently reported adverse events were common cold (FP 17 and SFP 28 patients) and headache (FP 21 and SFP 14 patients). In both groups one patient reported oropharyngeal candidiasis. DISCUSSION Based on our predefined criterion for demonstrating noninferiority we conclude that addition of the long-acting bronchodilator salmeterol is not inferior to doubling the dose of inhaled corticosteroid regarding symptomatic control during 6 months of treatment in school children with asthma still symptomatic on a moderate dose of inhaled corticosteroid. Also, lung function parameter outcomes were similar for the two treatment regimens. Although differences in response might be expected, depending on the level of baseline bronchoconstriction and airway inflammation, subgroup analyses revealed no differences. Compared with asthma guidelines for adults, the position of long-acting bronchodilators in the treatment of childhood asthma is less clear. Adult studies comparing doubling doses of inhaled corticosteroids to adding a long-acting bronchodilator unanimously are in favor of the latter strategy (16, 17). However, a 10 15% increase in FEV 1 after the use of a bronchodilator is usually one of the inclusion criteria, which might favor the effect of a long-acting bronchodilator (18). In children, several studies have been published comparing the addition of a long-acting bronchodilator with a moderate dose of inhaled corticosteroid with the same dose of inhaled corticosteroid. The effects on PEF rates are positive with addition of salmeterol (19, 20) and formoterol (21, 22), although effects on symptoms and exacerbations are usually not significant between treatment groups. Moreover, Bisgaard suggested that even an increased risk of exacerbations occurred when adding a long-acting bronchodilator in analyzing data from eight pediatric studies (23). A recent Cochrane analysis (9), however, concluded that compared with inhaled corticosteroids alone, the addition of a long-acting bronchodilator was not associated with an increase in exacerbations requiring oral steroids or hospitalization. Regarding the comparison of addition of a long-acting bronchodilator with doubling the dose of the inhaled corticosteroid only limited studies in children are available. Our former study compared beclomethasone, 400 mg daily, with the same dose plus additional salmeterol and doubling the dose of beclomethasone in children with moderate asthma (24). At the end of the 1-year study period no differences were found between treatment groups for lung function parameters (FEV 1 and PD 20 ); symptom scores; and exacerbations. However, PEF rates were slightly higher in the first months for the salmeterol group. Growth was significantly lower in the group with the high-dose beclomethasone. Inclusion criteria for this study were based on lung function parameters, requiring at least 10% reversibility of FEV 1. Because considerable improvements were seen in all treatment groups and compliance rates with medication were nearly 90%, it was concluded that probably this latter phenomenon resulted in daily doses of beclomethasone already on the plateau phase of the dose response curve in all treatment arms, thereby explaining the lack of difference between groups. A limitation of our current study is that no comparison was made with a lower dose of inhaled corticosteroid. However, with the run-in period of 4 weeks with a substantial number of children not to be randomized because of lack of symptoms, we attempted to select those children who really stayed symptomatic despite the use of 200 mg of fluticasone daily. Those children uncompliant with medication in daily life, who improved their compliance during the run-in period, would have gained substantial symptom improvement in this time interval, and so would not be eligible for randomization. We would also argue that the substantial improvement in the fluticasone group suggests that these children did not already reach the plateau-phase for the dose response curve at lower doses of inhaled corticosteroids (25).

5 Vaessen-Verberne, van den Berg, van Nierop, et al.: Doubling Dose of Inhaled Corticosteroid or Addition of Salmeterol 1225 TABLE 2. LUNG FUNCTION PARAMETERS AT BASELINE AND AFTER 1, 6, 16, AND 26 WEEKS OF TREATMENT FOR THE FLUTICASONE GROUP AND SALMETEROL/FLUTICASONE PROPIONATE GROUP Parameter Fluticasone (n 5 80) Salmeterol/Fluticasone Propionate (n 5 78) Adjusted Mean Treatment Difference (95% confidence interval) P Value FEV 1 % predicted Baseline (13.9) 99.4 (15.1) Week (14.9) 99.6 (16.4) 1.4 (21.9 to 4.7) 0.42 Week (13.4) (15.2) 0.1 (22.6 to 2.8) 0.95 Week (13.5) 100 (15) 1.6 (21.3 to 4.6) 0.28 Week (14.2) (14.7) 21 (24.1 to 2.2) 0.54 FVC % predicted Baseline (12.1) 99.1 (12.5) Week (11.6) 97.2 (14.0) 2.3 (20.3 to 4.8) 0.08 Week (11.1) (14.1) 0.3 (22.4 to 3) 0.84 Week (10.5) 98 (12.5) 0.7 (21.7 to 3) 0.57 Week (11.8) 98.4 (12.5) 21.2 (24 to 1.6) 0.39 Maximal expiratory flow % predicted Baseline 75 (20.5) 77 (22.3) Week (19.1) 84.2 (25.5) 26 (211.2 to 20.7) 0.03 Week 6 78 (19.4) 83.6 (21.7) 24.2 (29.1 to 0.7) 0.09 Week (19) 84.9 (24.1) 23.2 (28.5 to 2.1) 0.24 Week (20) 83.5 (21.6) 21.5 (26.3 to 3.4) 0.56 PEF rate % predicted Baseline 92.6 (15.1) 91.8 (16.4) Week (16.1) 94.7 (19.9) 20.6 (24.6 to 3.4) 0.76 Week (17.3) 96 (17.3) 21.1 (25.3 to 3.2) 0.63 Week (16) 96.7 (17.2) 21.6 (25.9 to 2.8) 0.48 Week (15.7) 96.3 (16) 22.7 (26.7 to 1.4) 0.20 PD 20 mg Baseline 107 (0.9 to.1570) 55 (3.9 to.1570) Week (0.8 to.1570) 313 (0.3 to.1570) 20.2 (21.6 to 1.2)* 0.79 Exhaled nitric oxide, ppb Baseline 12.8 (2.6 to 32.3) 11 (3 to 106) Week (1.8 to 51.6) 9.8 (1.9 to 64) 1.1 (0.8 to 1.6) 0.52 Values are expressed as means (SD) or median (range). Mean differences (fluticasone minus salmeterol/fluticasone propionate) shown are analysis of variance estimates from the intention-to-treat analyses with adjustment for sex, age, center, and baseline values. * Change from baseline, expressed as doubling dose. Ratio of geometric means. Recently, two pediatric studies have been published comparing the addition of salmeterol to inhaled corticosteroid (FP, 100 mg twice a day) with doubling the inhaled corticosteroid dose to 200 mg twice a day in children symptomatic on low moderate doses of inhaled corticosteroid (26, 27). Both studies were designed as noninferiority studies. A substantial proportion of patients recruited did not pass the run-in period for not fulfilling the inclusion criterion on symptom scores. This is in agreement with our study and may be explained by the increased compliance of children entering the run-in phase of a study compared with daily life, resulting in improvement of control status. In the 12-week study of De Blic and coworkers (26) as in the 8-week study of Gappa and coworkers (27) PEF rates were chosen as the primary outcome and turned out to be slightly higher in the salmeterol group. These positive results compared with our results may be explained by their inclusion criterion of reversibility, thereby favoring the effect of a longacting bronchodilator. Because the accuracy of PEF measurements has been argued, it could be discussed whether PEF rates should be the primary outcome measure in these studies (28). We therefore choose for our primary outcome parameter percentage symptom-free days during a prolonged period of 10 weeks, an important parameter of asthma control, which is considered the primary goal for treatment in recent guidelines (1, 2). To prevent a favorable effect of salmeterol addition, we did not select our patients on the basis of reversibility to a bronchodilator, but selected children solely on their control status (e.g., experiencing sufficient symptoms to warrant step-up treatment). The PACT study compared lower doses of fluticasone (100 mg twice a day) with fluticasone/salmeterol, 100/50 mg in the morning, and salmeterol, 50 mg in the evening, and with montelukast, 5 mg in the evening, in 285 children with mild moderate asthma (29). Fluticasone and the combination therapy TABLE 3. SUBGROUP ANALYSES FOR THE PERCENTAGE OF SYMPTOM-FREE DAYS DURING WEEKS 16 26, ACCORDING TO BASELINE FEV 1 (BELOW AND ABOVE MEDIAN: MEDIAN VALUE OF FEV % PREDICTED 100) AND BASELINE EXHALED NITRIC OXIDE (BELOW AND ABOVE MEDIAN: MEDIAN VALUE OF EXHALED NITRIC OXIDE 11.5 PPB) Subgroup Mean Adjusted Difference Between Treatment Groups (95% confidence interval) P Value P Value for Difference Between Subgroups FEV 1 below median, n (214 to 16) 0.87 FEV 1 above median, n (216 to 10) Exhaled nitric oxide below median, n (234 to 14) 0.40 Exhaled nitric oxide above median, n (224 to 28) Mean differences (fluticasone propionate minus salmeterol/fluticasone propionate) within the subgroups of percentage symptom-free days shown are analysis of variance estimates with adjustment for baseline value, age, sex, and center.

6 1226 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL arm were identical in terms of asthma control including exacerbations, but fluticasone was superior for lung function parameters as FEV 1 /FVC, PC 20, and FeNO. Children in this study were included on the basis of symptoms, FEV 1 greater than or equal to 80% predicted, and airway responsiveness. This might have influenced their response on inhaled corticosteroids. On the other hand, combination therapy in this study was incomplete, because the evening dose of salmeterol was not combined with inhaled corticosteroid. Data from several studies do suggest that the combination of salmeterol and inhaled corticosteroid from the same inhaler is more efficient than from separate inhalers, thereby suggesting a synergistic effect of the combination therapy (30). A triple crossover study comparing step-up treatment with salmeterol, montelukast, or additional fluticasone in children with symptomatic asthma showed that addition of a long-acting bronchodilator provided most likely the best response in terms of asthma control days (31). However, part of the children had better responses to either addition of inhaled corticosteroid or montelukast (about 30% of children for either treatment). Except for a higher baseline score on the Asthma Control Test and white race, no other predictive factors for a favorable response to a long-acting bronchodilator could be identified. The number of oral corticosteroid courses did not differ between treatments, but was much higher compared with our study. Because criteria for starting prednisolone were explicit for children and parents and more rigid than in our study, this may have resulted in more contacts with their treating physicians and therefore prescriptions than in our study. Regarding the safety issue of long-acting b 2 -agonists and exacerbations, in our 26-week study severe exacerbations were rare (only two) and both were in the SFP group, in which also the number of oral corticosteroid courses was higher, although not statistically significant different from the FP group. Our data are in line with the trend in the Cochrane review (9), but are not supported by the data from the Lemanske and coworkers study (31). Because the number of children in all of these individual studies might be too small especially to detect any difference in severe exacerbations, further data are necessary to make definite conclusions about a possibly increased risk for oral steroids and hospital admissions with the use of long-acting b 2 -agonists in children. Our study indicates that the efficacy of the combination of salmeterol/fluticasone is equal to doubling the dose of fluticasone regarding symptom control and lung function in children with moderate asthma who are still symptomatic on moderate doses of inhaled corticosteroid. Further studies are necessary to find out whether specific phenotypes favor more from one of the treatment options. Author Disclosure: A.A.P.H.V-V. received $10,001 $50,000 from GlaxoSmithKline in institutional grants. N.J.V.D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.V.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.J.L.B. received $1,001 $5,000 from GlaxoSmithKline for serving on an advisory board; $1,001 $5,000 from GlaxoSmithKline in lecture fees for nonpromotional CME-activity; and $5,001 $10,000 from GlaxoSmithKline in institutional grants as compensation for costs involving participation in multicenter studies. G.P.J.M.G. received up to $1,000 from GlaxoSmithKline in lecture fees and up to $1,000 from Novartis in lecture fees for a writing congress summary. W.C.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.J.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Members of the COMBO Study Group include the following: Medical Center, Alkmaar (G. Brinkhorst, M.D.); Flevo Hospital, Almere (N.J. van den Berg, M.D.); Department of Pediatric Respiratory Diseases, Academic Medical Center/Emma s Children s Hospital, Amsterdam ( J.C. van Nierop, M.D.); Rijnstate Hospital, Arnhem (A.M. Landstra, M.D., Ph.D.); Amphia Hospital, Breda (A.A.P.H. Vaessen- Verberne, M.D., Ph.D., and M.C. Kuethe, M.D.); Catharina Hospital, Eindhoven (H.J.L. Brackel, M.D., Ph.D.); Medisch Spectrum Twente, Enschede (B.J. Thio, M.D., Ph.D.); Groene Hart Hospital, Gouda (F.G.A. Versteegh, M.D., Ph.D.); Department of Pediatric Respiratory Diseases, University Medical Center Groningen/ Beatrix Children s Hospital, University Groningen (E.J. Duiverman, M.D., Ph.D.); Juliana Children s Hospital, The Hague (M. Nuijsink, M.D., and J.M. Kouwenberg, M.D.); Elkerliek Hospital, Helmond (R.P. Droog, M.D.); Westfries Gasthuis, Hoorn (P.C. Overberg, M.D.); Medical Center Leeuwaren, Leeuwarden (T.W. de Vries, M.D., Ph.D.); Department of Pediatric Respiratory Diseases, University Hospital Maastricht ( J.J.E. Hendriks, M.D., Ph.D., and Q. Jöbsis, M.D., Ph.D.); Canisius Wilhelmina Hospital, Nijmegen (G.P.J.M. Gerrits, M.D., Ph.D.); Department of Biostatistics, Erasmus University Medical Center, Rotterdam (W.C.J. Hop, Ph.D.); Maasland Hospital, Sittard (J.W.C.M. Heijnens, M.D.); Department of Pediatric Respiratory Diseases, University Medical Center/Wilhelmina Children s Hospital, Utrecht (C.K. van der Ent, M.D., Ph.D.); Maxima Medical Center, Veldhoven (R. van Gent, M.D., Ph.D.); and Isala Klinieken, Zwolle (P.L.P. Brand, M.D., Ph.D.) all from the Netherlands. References 1. 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