INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Cough and wheezing are very common in children younger than 4 yr of age and are a major cause of illness and admissions to hospital. Up to 40% of all children are reported to have wheezing disorders during the first 3 yr of life (1). Recent longitudinal studies indicate that approximtely 60% of wheeze occurring in the first 3 yr of life is transient and benign, and may disappear by the age of 6 yr (2, 3). It is suggested that this group of children have congenitally narrow airways, which predisposes them to wheezing in association with viral infections in early life (4). Most children who develop chronic asthma in later childhood will have had their first symptoms during the first 3 yr of life (5). These infants have most of the risk factors associated with asthma (high serum IgE levels, positive skin test reactivity to allergens, bronchial hyperresponsiveness, family history of asthma) and, although they do not have reduced lung function as a predisposing factor, their lung function is diminished by 6 yr of age. Diagnosis of asthma is ambiguous, and objective supportive evidence for the diagnosis is missing. At present the diagnosis of asthma in young children can only be delineated empirically, and carries no implication for prognosis or underlying pathology.

Children younger than 4 yr of age with wheeze or asthma are a difficult population in which to conduct clinical studies because of the variable nature of the symptoms and the limited outcome measures. Since the first placebo-controlled study of inhaled corticosteroid in young asthmatic children under 4 yr of age (6), a number of clinical trials with inhaled corticosteroids have been performed in these age groups. Efficacy of inhaled corticosteroids has been documented in asthmatic children younger than 4 yr of age with moderate to severe persistent asthma symptoms (6). Sodium cromoglycate was recently reported to be ineffective in a large parallel study of 167 young children with moderate persistent asthmatic symptoms, very similar to the present design (9). In the case of episodic viral wheeze in preschool children, modest improvements have been shown with intermittent high-dose inhaled corticosteroids (10, 11), but continuous prophylactic treatment showed no effect (12).

Daily doses of 800 µg budesonide from a pressurized metered dose inhaler (pMDI) and spacer or 2,000 µg from a nebulizer were used in the studies documenting the effect of inhaled corticosteroids in asthmatics younger than 4 yr of age. The high doses used in the treatment of persistent young asthmatics were justified in such pioneering studies aiming to establish a new treatment modality, but should not be used as guideline for the dose range required to control asthma in young children.

No formal dose response studies of inhaled steroids have been performed in preschool children, so the optimal dose in these age groups is not known. In the present study we have sought to elucidate the dose response to inhaled corticosteroids within a pediatric dose range for the treatment of young children with asthmatic symptoms. We have compared the effect of fluticasone propionate (FP) (Glaxo Wellcome, UK) inhaled from a Babyhaler spacer device (Glaxo Wellcome, UK) in a daily dose of 100 µg (FP100) with that of 200 µg (FP200) and with placebo in parallel groups of young children age 1 to 3 yr with a history of moderate asthmatic symptoms.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Pediatric outpatients age 12 to 47 mo with a documented history of recurrent wheeze or asthma symptoms were recruited for the study. Patients were randomized to the study if, on at least 7 d out of the last 14 d of the run-in period, they had any asthmatic symptoms, as recorded in three symptom domains (wheeze, cough, and shortness of breath) for daytime and nighttime separately, or had required relief salbutamol. Patients were excluded if, in the 2 wk before entering the run-in period, they received inhaled or systemic corticosteroids or methylxanthine therapy, had been hospitalized for asthma, had any changes in asthma medication, or if they had received antibiotics for a chest infection. Patients were also excluded if, after practicing inhalation technique during the run-in period, they were unable to use the Babyhaler device correctly.

This was a randomized, double blind, placebo-controlled parallel group study, with patients recruited from 33 centers in nine countries (as listed in the ACKNOWLEDGMENT). Patients who fulfilled the inclusion and exclusion criteria entered a 4-wk run-in period, during which they received two puffs twice daily of placebo from a pMDI, via the Babyhaler spacer, and salbutamol as required to relieve symptoms. At the end of the run-in period, patients who fulfilled the eligibility criteria were randomly assigned to receive either two puffs of FP 25 µg twice daily (total daily dose of 100 µg [FP100]), or two puffs of FP 50 µg twice daily (total daily dose of 200 µg [FP200]), or two puffs of placebo twice daily via identical CFC-formulated pMDIs delivered through a Babyhaler spacer device. Parents were taught to actuate the trial inhaler once the spacer was in position, with the face mask over the child's nose and mouth, and then to allow at least five tidal breaths (or 15 s) for inhalation. This procedure was then repeated for the second puff. No instructions were given on priming of the Babyhaler before use, although during use, parents were instructed to wash it once a week in mild soapy water, followed by rinsing and leaving it to dry. Patient compliance was carefully checked at the clinic visits every 3 wk, though not quantitated.

Salbutamol was used throughout the study as relief medication in a formulation appropriate to each child: either inhaled from a pMDI (100 µg salbutamol per actuation) via the Babyhaler; or as dry powder (200 µg salbutamol per blister) inhaled using a Diskhaler; or nebulized using Ventolin Nebules (2.5 mg/2.5 ml salbutamol); or orally as Ventolin Syrup (2.0 mg/5 ml salbutamol). Patients continued with any regular medication, including sodium cromoglycate, ketotifen, and antihistamines, for asthma or other conditions providing the dose remained constant. Inhaled or systemic corticosteroids, anticholinergic agents, nedocromil sodium, ₂-agonists (other than salbutamol supplied for rescue medication), and methylxanthine derivatives were not permitted, unless for treatment of an exacerbation. Regulatory approval was obtained in those countries where it was required, and ethics committee approval was obtained for each site before the start of the study. A parent or guardian of every patient provided written informed consent.

Assessments were performed in the clinic at the beginning and end of the placebo run-in period and thereafter every 3 wk for a total treatment period of 12 wk. At the first clinic visit, demographic details and a full clinical history were recorded, and a physical examination was performed. On randomization, pulmonary auscultation was conducted, and parents were given a questionnaire about the child's asthma symptoms, the impact of the child's asthma symptoms on the parents' activities in and around the house, leisure activities, work activities, the need for alternative childcare arrangements, and the overall control of asthmatic symptoms. This questionnaire was repeated at the end of treatment. At every clinic visit throughout the study, adverse events, asthma exacerbations, and compliance with the study protocol, including inhalation technique, were checked and the oropharynx was examined, with a swab taken if there was visual evidence of fungal infection, to determine the presence of candida.

Throughout the study, parents kept daily record cards of their child's symptoms, recording daytime and nighttime scores for wheeze, cough, and shortness of breath on a scale of 0 to 3. Parents were asked to record the number of occasions during the night that they were awoken because of the child's asthma symptoms. The number of occasions on which rescue salbutamol was used to relieve asthma symptoms during each day and night was also recorded.

Exacerbation of asthma was defined as a worsening of the child's asthmatic symptoms that required either a change in medication (other than relief salbutamol) and/or required the parents to contact their general practitioner or the investigator. Treatment of the exacerbation was at the discretion of the investigator, and could include a short course of inhaled or oral corticosteroids if needed. Patients were withdrawn from the study if more than one exacerbation occurred that required extra oral or inhaled corticosteroids, or if symptoms became unacceptable or poorly controlled despite backup medication. All analyses were performed on the intention-to-treat population, which consisted of all randomized patients who took at least one dose of study medication. The primary measures of efficacy were the percentages of cough-free and wheeze-free days, derived from the daily diary card data, over treatment wk 1 to 12. Secondary measures of efficacy included percentage of nights without cough or wheeze, percentage of days/nights without relief salbutamol medication, percentage of overall symptom-free days and nights, and percentage of nights without parental sleep disturbance, as well as the incidence of exacerbations and data from the parental questionnaires. All daily diary card variables were analyzed as change from baseline. Baseline was taken as the last 2 wk of the run-in period, which was also the period evaluated before randomization to determine if the child was eligible for the study.

A nonparametric method (the Van Elteren extension to the Wilcoxon rank sum test) was used for each variable to assess pairwise differences between the treatment groups over the treatment period. Mann-Whitney rank sum test was used to compare exacerbation rates in the three treatment groups. Kaplan-Meier estimates of survival times were used to compare times to first exacerbation. Treatment differences were assessed using two-sided significance tests, based at the 5% level of significance. The sample size for this study was based on the nonparametric analysis of the percentage of asthma symptom-free days during treatment. Based on a standard deviation of 29% (shown in a previous pilot study), it was calculated that 70 children per treatment group were needed to detect a treatment difference of 15% between groups, with 80% power at the 5% level of significance.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

A total of 314 patients were recruited to the study of which 237 were randomized to treatment and comprised the intention-to-treat population (Figure 1). The majority of the 77 patients withdrawn prior to randomization were withdrawn because they had insufficient asthma symptoms, others for reason of asthma exacerbations. Thirty-seven randomized children violated the protocol, equally distributed among treatment groups (12 placebo, 12 FP100, 13 FP200). Reasons for classification as a protocol violator included age violation (four patients), insufficient symptoms or insufficient salbutamol usage during run-in (18 patients), respiratory tract infections requiring antibiotics, asthma medication changes or hospitalization during run-in (four patients), failing to have diary card data from at least 50% of the treatment period (11 patients), and taking disallowed concurrent medications during the treatment period (four patients). Two patients were withdrawn during the study by the investigator for reason of noncompliance. However, the analysis was done on the intention-to-treat group of children including all protocol violators.

View larger version (35K): [in this window] [in a new window]   Figure 1.   Patient flow through the study.

The mean age across all three groups was 28 mo (range 12 to 47 mo). Pretreatment characteristics (Table 1), including weight, height, asthma history, current medical condition, and current medications, were all generally comparable among the groups. The study group of children appeared to have moderately severe recurrent asthmatic symptoms. During the run-in period, the children had symptoms on a median of 81% of days, and salbutamol was used on a median of 48% of days. Forty-six percent had had 1 to 3 exacerbations, and 38% more than 3 exacerbations during the previous year. Sixty-eight percent had not been hospitalized for asthma-related symptoms, 17% only once, and 15% more than once during the previous year. Fifty-three percent of the study group had had asthmatic symptoms for more than 12 mo. A total of 57 patients (24%) were receiving sodium cromoglycate on entry to the study and 18 patients (7%) were receiving ketotifen, and these patients all continued on these medications during the treatment period. Over all patients, current asthma control on entry into the study was rated as 7 by the parents on a scale from 1 (poorly controlled) to 10 (well controlled). The groups differed at baseline. The percentages of days with no cough during the run-in period were 41%, 31%, and 29% in the placebo, FP100, and FP200 groups, respectively. The corresponding percentages of days with no symptoms of any type were 21%, 14%, and 7%. The placebo group used salbutamol on 43% of the days, whereas the FP200 group used salbutamol on 64% of the days during run-in. A similar trend was consistent throughout the secondary efficacy variables, and indicated that the placebo group had fewer and milder symptoms at baseline.

Figure 2 illustrates the median differences in the changes from baseline, and the 95% confidence limits (CL), between active and placebo treatments for the various diary card parameters. FP200 produced a significant reduction in 8 of 10 diary card parameters compared with placebo, whereas FP100 produced a significant reduction in 5 of 10 parameters compared with placebo. No significant differences were found between FP200 and FP100. The treatment effect was most clearly revealed by reduction in cough and use of salbutamol. Wheeze and shortness of breath also exhibited significant improvement in the actively treated children compared with placebo treatment, although the numbers of patients recording these particular symptoms at baseline were relatively low. The development in symptom-free days is illustrated in Figure 3.

View larger version (22K): [in this window] [in a new window]   Figure 2.   Changes from baseline. Differences between the FP group and the placebo group. Median (95% CL). Eight of 10 diary card parameters showed significant improvement from FP200 compared with placebo, and 5 of 10 showed significant improvement from FP100 compared with placebo.

View larger version (24K): [in this window] [in a new window]   Figure 3.   Percentage of symptom-free days (median change from baseline).

The number of patients with at least one exacerbation during the treatment period was found to be significantly lower in the FP200 treatment group (15 of 76 patients; 20%) compared with the placebo group (30 of 82 patients; 37%), p = 0.03, 95% CL for the difference 2 to 32% (Figure 4). Using Kaplan-Meier estimates of survival times, there was a significant difference in the distribution of times to first exacerbation between the FP200 group and the placebo group (p = 0.022), indicating a smaller likelihood of exacerbation in the FP200 group.

View larger version (26K): [in this window] [in a new window]   Figure 4.   Exacerbation rate. Dose relation is significant, p < 0.05.

The number of children in the FP100 group who experienced exacerbations (21 of 80 patients; 26%) was also lower than in the placebo-treated group. The dose-related effect on exacerbation rate was significant (p < 0.05). This difference in exacerbation rate became apparent early during the study, with 10 (12%) of the placebo patients exacerbating during the first 2 wk of treatment compared with 7 (9%) in the FP100 group and 3 (4%) in the FP200 group. Rescue treatment with corticosteroids was required in 16% of the patients in the placebo group compared with 5% in the FP100 group, and 5% in the FP200 group, and these differences were statistically significant. (FP200 versus placebo: p = 0.039; FP100 versus placebo: p = 0.038).

The number of patient withdrawals did not differ significantly among the three treatment groups, with 8, 7, and 10 withdrawals from the treatment groups of placebo, FP100, and FP200 respectively (Figure 1). On randomization into the study, parents were asked to rate their child's asthma symptoms as either "much better," somewhat better," "about the same," "somewhat worse," or "much worse" than 3 mo ago. The findings revealed a median score of "somewhat better" compared with 3 mo ago. Asked the same question at the end of the 12-wk treatment period, there was a 20%, 43%, and 37% increase in the rating of asthma as "much better" in the placebo, FP100, and FP200 groups, respectively. The scores for the parental rating of symptom control were statistically significantly more favorable for the FP200 group compared with the placebo group (p = 0.03). There were no statistically significant differences between the FP100 group and placebo or between the two FP groups.

The parents rated the current asthma symptoms on a scale control from 1 (poorly controlled) to 10 (well controlled). In all three treatment groups, the median score on entrance into the study was 7 and improvements were seen in all three treatment groups at completion of the treatment, with a median score of 9. In the placebo group there was a 12% increase in the number of parents reporting current asthma symptoms as "well controlled," with 18% and 22% increase in the FP100 and FP200, groups, respectively. However, there were no statistically significant differences (placebo versus FP200, p = 0.06). Impact on parents' activities in and around the house, leisure activities, work activities, the need for alternative childcare arrangements, and the overall control of asthma symptoms consistently showed trends of increased improvement in the active treatment groups, but there were no statistically significant differences.

A total of 68 patients treated with placebo, 63 patients treated with FP100, and 64 patients treated with FP200 reported adverse events during treatment. The adverse event profile did not differ markedly among the three treatment groups. Asthma was the most commonly reported adverse event, being reported by 21 patients (26%), 18 patients (23%), and 13 patients (17%) in the placebo, FP100, and FP200 treatment groups, respectively. Fever and upper respiratory tract infections were also commonly reported.

Of the events considered predictable, skin rashes were reported in two patients (2%) on placebo, two (3%) on FP100, and four (5%) on FP200. Throat irritation was reported in two patients (2%) on placebo, two (3%) on FP100, and four (5%) on FP200. Hoarseness/dysphonia was reported in only two patients, both on FP100, and candidiasis of the mouth/throat was reported as an adverse event in only one patient, who was receiving placebo.

Visual evidence of oral candida was observed during the treatment period in 6% of children on placebo, 10% of children on FP100, and 4% of children on FP200. Fourteen patients experienced serious adverse events during the treatment period, seven (9%) receiving placebo, two (3%) receiving FP100, and five (7%) receiving FP200. The most common serious adverse event was asthma reported in four patients (5%) in placebo, two (3%) on FP100, and two (3%) on FP200. Of the three serious adverse events on FP200 not related to asthma, one was a case of gastritis, one presented with fever, and one had diarrhea.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Toddlers 1 to 3 yr of age with moderate asthmatic symptoms improved significantly from 12 wk treatment with FP 100 µg twice daily inhaled from the Babyhaler spacer device. A clinical effect became apparent within 2 wk of starting treatment, as indicated by differences in exacerbation rate and days without symptoms. The treatment was dose-related and well tolerated in the usual pediatric dose range of 100 to 200 µg daily dose of FP.

The present study group comprised young children of 1 to 3 yr of age with a documented history of recurrent wheeze and other asthma symptoms. Because there is no consensus on the definition of asthma in young children, there is no recognized grading of the disease severity either. If the grading of intensity of symptoms and use of rescue medication in schoolchildren is applied, these children had moderate asthma. During the run-in period, rescue salbutamol medication was used on approximately 1 of 2 d, and the children were symptomatic on 4 of 5 d. The history attested to the persistence of symptoms with, on average, 3 exacerbations during the previous year and one-third of the children having been hospitalized for this reason.

FP200 resulted in significant improvement in 8 of 10 diary card parameters, including all three symptom domains of cough, wheeze, shortness of breath, and in the use of salbutamol and parental sleep disturbance. FP100 produced significant improvement in 5 of the 10 diary card parameters. A significant dose-related effect was observed in the number of exacerbations, which is a key outcome measure. It cannot be known if higher doses would lead to further improvement.

Disease control, evaluated from percentage of days and nights with no symptoms, was significantly higher in the FP200 treatment group than in the placebo group (median difference in change from baseline = 11%). The incidence of exacerbations was 37% in the placebo group compared with 20% in the FP200 group. These results confirm the concept that inhaled corticosteroids within a pediatric dose range are efficacious in young children with moderate persistent asthmatic symptoms. However, in clinical practice an improvement of this magnitude may be insufficient to warrant continued treatment of the whole group of children. The treatment effect is probably driven by a subgroup of children responding to inhaled corticosteroid treatment, whereas other children with apparently comparable symptoms may profit less or not at all. We are at present unable to predict who will respond to treatment. The clinical implication of the present data is therefore that children with moderate asthmatic symptoms may respond to treatment with inhaled FP 100 µg twice daily. A therapeutic trial of 1 to 2 mo may be a feasible approach to help determine the optimal treatment of the individual child. Scheduled follow-up visits should ascertain if control is obtained. If convincing control is not obtained, treatment should obviously not be maintained. If control of symptoms does occur, withdrawal or dose reduction should be attempted to ascertain the continued need for treatment at the minimal dose level. This would ensure that treatment with inhaled corticosteroids is only provided to those deriving benefit. Further, a determined attempt to down-titrate the dose toward no treatment or to the minimal effective dose assures that no child is kept on inhaled corticosteroids longer than needed. A similar approach is reflected in the recent guidelines from the British Thoracic Society (13).

In the present study, FP200 was as well tolerated as placebo and no unexpected side effects became apparent over this 12-wk observation period. A knemometry study in 1 to 3-yr-old toddlers has demonstrated systemic activity with inhaled FP 400 µg daily (twice the daily dosage of the present study) as well as from inhaled budesonide 400 µg daily (14). Budesonide was without systemic activity in a daily dose of 200 µg in a previous knemometry study (15), but clinical efficacy at such a dose of budesonide remains to be documented. The present study documents clinical efficacy from 200 µg daily dose of FP, but lack of systemic activity at this dose remains to be documented. The use of inhaled corticosteroids in young children should be restricted to experienced doctors until more evidence of the safety of this treatment is obtained.

Dedicated spacer devices for drug delivery to young children have recently become available, and have facilitated the treatment of this poorly compliant patient group (16). This study confirmed spacer with pMDI as a convenient device able to deliver a clinically efficacious dose of aerosol to young children.

In conclusion, this study showed a significant clinical effect from both FP200 and FP100 delivered via the Babyhaler spacer device in the treatment of asthmatic symptoms in 1- to 3-yr-old children, with a dose-related effect and with FP200 as the most effective dose. Symptom control was obtained in some children even in the low dose, and the dose-related response indicates that dose requirement should be titrated individually. These findings support the option of inhaled corticosteroid treatment for asthmatic symptoms in young children.