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1 Karolinska Hospital, Stockholm, Sweden, 2 Mainz University Hospital, Germany, 3 Ullevål Hospital, Oslo, Norway, 4 La Fe University Hospital, Valencia, Spain, 5 Päijät-Häme Central Hospital, Lahti, Finland, 6 Beaumont Hospital, Dublin, Ireland and 7 AstraZeneca, Lund, Sweden
CORRESPONDENCE: O. Zetterström, Karolinska Sjukhuset, Allergicentrum Universitetssjukhuset, S-581 85, Linköping, Sweden.
Keywords: asthma, budesonide, formoterol, glucocorticosteroids, inhalation
Received: July 21, 2000
Accepted March 28, 2001
This study was supported by AstraZeneca, Lund, Sweden.
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Abstract |
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In this 12-week, double-blind, randomized, double-dummy study, 362 adult asthmatics (forced expiratory volume in one second 73.8% of predicted, inhaled glucocorticosteroid dose 960 µg·day–1) received single inhaler budesonide/formoterol (Symbicort® Turbuhaler®) 160/4.5 µg, two inhalations b.i.d., or corresponding treatment with budesonide, or budesonide plus formoterol via separate inhalers.
There was a greater increase in morning peak expiratory flow (PEF) with single-inhaler (35.7 L·min–1) and separate-inhaler (32.0 L·min–1) budesonide and formoterol, compared with budesonide alone (0.2 L·min–1; p<0.001, both comparisons); the effect was apparent after 1 day (p<0.001 versus budesonide, both comparisons). Similarly, evening PEF, use of rescue medication, total asthma symptom scores and percentage of symptom-free days improved more with both single inhaler and separate inhaler therapy than with budesonide alone, as did asthma control days (
15% more, p<0.001 versus budesonide, both comparisons, with a marked increase in the first week). All treatments were well tolerated and the adverse event profile was similar in all three treatment groups.
It is concluded that single inhaler therapy with budesonide and formoterol is a clinically effective and well-tolerated treatment for patients with asthma that is not fully controlled by inhaled glucocorticosteroids alone.
Effective control of asthma symptoms and maintenance of optimal lung function are critical for the long-term management of patients with persistent asthma. The use of inhaled glucocorticosteroids as first-line treatment for the management of patients with all but intermittent asthma is firmly established 1–3. However, many patients taking inhaled glucocorticosteroids still suffer from asthma symptoms and exacerbations necessitating use of relief medication with short-acting ß2-agonists. Increasing use of short-acting ß2-agonists is often associated with poor asthma control. Moreover, the regular use of short-acting ß2-agonists has been questioned 4.
In patients receiving inhaled glucocorticosteroids whose asthma is not fully controlled, national and international guidelines recommend a step-wise approach 1–3. Increasing the dose of inhaled glucocorticosteroid or, alternatively, the addition of a long-acting ß2-agonist to low-dose inhaled glucocorticosteroids are two therapeutic options. Recent evidence suggests that the addition of a long-acting ß2-agonist to inhaled glucocorticosteroids may be more beneficial in terms of asthma control than increasing the dose of corticosteroids alone 5–7. The long-term use of long-acting ß2-agonists has been challenged with respect to their potential to mask the progression of airway inflammation and thereby worsen asthma 8.
In the recent long-term study by Pauwels et al. 9, the addition of the long-acting ß2-agonist formoterol to budesonide (high or low dose) for 1 yr improved asthma symptoms and lung function without any deterioration in asthma control 9. Formoterol decreased the incidence of both mild and severe asthma exacerbations independent of the dose of budesonide. However, a higher dose of budesonide plus formoterol resulted in the greatest reduction in the rate of severe exacerbations 9. A second 1-yr study, by Kips et al. 10, showed that adding formoterol to low-dose budesonide treatment in patients with moderate asthma did not lead to a significant increase in sputum markers of airway inflammation compared with a four-fold higher dose of budesonide treatment alone. From these studies, it is apparent that the addition of formoterol to budesonide in patients whose asthma is not fully controlled, offers the potential to optimize control of asthma.
This study is the first to report the efficacy and safety of the new single Turbuhaler® inhaler therapy, Symbicort®. The single inhaler containing budesonide and formoterol, and the concurrent administration of budesonide and formoterol in two separate inhalers, were compared with budesonide alone in patients with symptomatic asthma despite previous regular treatment with inhaled glucocorticosteroids.
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Methods |
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18 yrs were eligible for inclusion in the study if: 1) they were using inhaled glucocorticosteroids at a constant daily dose of 500 µg for 30 days before entry; 2) they had a baseline forced expiratory volume in one second (FEV1) of 50–90% predicted; and 3) they had a reversibility from baseline of 15% after inhalation of terbutaline sulphate 1 mg (Bricanyl® Turbuhaler®) or salbutamol 0.4 mg.
Exclusion criteria included: use of oral, parenteral or rectal glucocorticosteroids within 30 days before study entry; respiratory infection; seasonal asthma; severe cardiovascular disorder; beta-blocker therapy; a history of heavy smoking (10 pack-yrs); pregnancy or failure to use acceptable contraceptives in women of childbearing potential.
The present study was conducted in accordance with the Declaration of Helsinki. The local ethics committees approved the study protocol and all patients gave written informed consent prior to study commencement.
Study design
This was a randomized, double-blind, double-dummy, active-controlled study with a parallel-group design conducted at 59 centres in Finland, Germany, Ireland, Norway, Spain and Sweden. At an initial visit (visit 1), patients underwent a physical examination and complete medical and respiratory histories were taken. This and subsequent visits (visits 2–5) took place between 07.00 and 10.00 h.
Computerized randomization occurred on a per-country basis and individual treatment codes were kept in sealed envelopes until data analysis. To ensure treatment blinding, the patients successively used three numbered inhalers (identical in appearance to the corresponding placebo) each morning and evening.
After a 2-week run-in period, during which the patients continued with their usual inhaled glucocorticosteroid therapy, patients were allocated to randomized treatment (two inhalations b.i.d.) for 12 weeks with the following: single inhaler therapy containing budesonide (160 µg) and formoterol (4.5 µg) (budesonide/formoterol; Symbicort® 160/4.5; AstraZeneca, Lund, Sweden); budesonide (200 µg) plus formoterol (4.5 µg) via separate inhalers; or budesonide (200 µg) alone. The new Turbuhaler® (single inhaler therapy) has a dose counter, an externally tapered mouthpiece, and measures dose as delivered dose. The original Turbuhaler® (budesonide alone) measured metered dose; hence the doses of budesonide in each treatment group were equivalent, as were the doses of formoterol.
No concomitant asthma medication, except rescue medication with terbutaline sulphate (Bricanyl® Turbuhaler®) or salbutamol, was allowed during the study. The need for oral corticosteroids led to withdrawal of the patient from the study. Inhalation technique of the patients was assessed at each clinic visit.
Efficacy assessments
Peak expiratory flow (PEF) measurements and severity of asthma symptoms were recorded each morning and evening by the patients on diary cards for the duration of the study. Baseline diary data for 7 of the last 10 days of run-in were required at randomization. PEF was measured using a mini-Wright® peak flow meter (Clement Clark, Harlow, UK) before intake of study medication, and the highest of three values was recorded. Daytime and night-time asthma symptoms were each graded on a scale of 0–3 (0=none; 1=mild; 2=moderate; 3=severe). Total asthma symptom score (on a scale of 0–6) was the sum of daytime and night-time symptoms scores. Symptom-free days were defined as days with a total asthma symptom score of 0 and no night-time awakening. Night-time awakenings due to asthma symptoms and use of rescue medication were also recorded. Asthma control days (from patients' diaries) were defined as days with no nocturnal awakenings, no asthma symptoms and no rescue medication use. Adherence to therapy was assessed by reviewing patient diary cards.
Subjects made five visits during treatment: an initial visit (visit 1), a second randomization visit (visit 2) and three visits at 4-weekly intervals (visits 3–5). Assessments of lung function as per the European Respiratory Society Recommendations 11 were performed at all visits. The highest values of 3 FEV1 and forced vital capacity (FVC) readings were recorded. A reversibility test was performed at visit 1 by measuring FEV1 before and after inhalation of terbutaline sulphate 1 mg or salbutamol 0.4 mg.
The number of severe and mild exacerbations during the 12-week period was also assessed. Severe exacerbations were defined as the need for oral steroids, discontinuation due to worsening of asthma, or PEF <70% of run-in mean on two consecutive days. Mild exacerbations were defined as two consecutive days with either: PEF <80% of the run-in mean, a 24-h period with 4 inhalations of reliever medication above the mean run-in use, night-time awakening due to asthma or any combination of the above.
Clinical safety assessments
Adverse events were recorded at visits 2–5, both spontaneously reported and in response to a standard question asked by the investigator. Laboratory assessments of clinical chemistry, haematology and urinalysis were conducted at the start and the end of the treatment period.
Statistical analysis
The primary efficacy variable was change in average morning PEF from baseline to study end. The primary objective was to compare the efficacy of the single inhaler (budesonide/formoterol) with that of budesonide alone. It was estimated that 100 subjects would be needed to detect a 20 L·min–1 difference between the treatments (budesonide/formoterol in a single inhaler versus budesonide alone) with a power of 80% at the 5% significance level, assuming a residual standard deviation of 50 L·min–1. An active control group was also included for safety and to compare the efficacy of budesonide plus formoterol administered via separate inhalers with that of budesonide alone. The study was not designed to detect differences between both single inhaler and separate inhaler budesonide and formoterol groups.
All efficacy variables were analysed on an intention-to-treat basis, using data from all patients who had taken 1 dose of study medication. For PEF measurements and other diary card variables, baseline was defined as the average over the last 10 days of run-in and treatment as the average over the entire treatment period. Changes from baseline were analysed by analysis of variance (ANOVA), with treatment and country as factors and the baseline value of the dependent variable as covariate. The spirometry variables measurements obtained at randomization (visit 2) were considered baseline values and baseline versus treatment results (last visit) were analysed in a multiplicative model, i.e. the logarithms of the values were subjected to an ANOVA similar to the one for diary-card variables, in order to allow comparison of percentage change rather than absolute change.
The time to first exacerbation was compared between groups using a log-rank test and further described as relative risk of an exacerbation using a Cox regression model with treatment as factor.
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Results |
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). The mean FEV1 was 73.8% pred, mean reversibility 22.5% and the mean dose of inhaled glucocorticosteroids 960 µg·day–1. Self-reported adherence to study medication was high (mean >98%) in all three treatment groups.
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Efficacy
Statistically significantly greater increases in morning and evening PEF were observed with single inhaler therapy (35.7 L·min–1 and 24.8 L·min–1, respectively) and separate inhaler therapy (32.0 L·min–1 and 22.3 L·min–1, respectively) than with budesonide alone (0.2 L·min–1 and –3.7 L·min–1, respectively; p<0.0001, both comparisons; table 2). The onset of effect with both single inhaler therapy and separate inhaler therapy on morning PEF was apparent from day 1 (p<0.0001 versus budesonide, both comparisons). However, during the first 30 days of treatment single inhaler therapy tended to show a more rapid improvement in both morning and evening PEF, compared with separate inhaler therapy (fig. 1). This trend in favour of the single inhaler therapy versus separate inhaler therapy approached significance for morning PEF (primary variable) during weeks 2 and 3 (p<0.07, post hoc analysis), with the size of the treatment difference ranging from 6–9 L·min–1 in each of the first 4 weeks.
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). Over the whole treatment period there was no statistically significant treatment difference between the single inhaler therapy group and those receiving separate inhaler therapy. Nevertheless, the change in total asthma symptom scores when plotted against time also showed that the reduction in asthma symptoms tended to be achieved more rapidly with single inhaler therapy compared with separate inhaler therapy (fig. 2).
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). Indeed, the benefits of both single inhaler therapy and separate inhaler therapy in this study were estimated to give patients 15% more asthma control days (p<0.001 versus budesonide) and more than doubled the number of control days versus baseline (table 2). Moreover, during the first week of treatment, 14.2% and 12.3% improvements in asthma control days were obtained in the single inhaler and separate inhaler groups, respectively (p<0.001 versus budesonide, both comparisons). This trend for a more rapid improvement in asthma control with the single inhaler versus separate inhaler therapy was also suggested by the Kaplan-Meier survival curves of the time to a first mild exacerbation in each study group (fig. 3). Overall, the Cox regression model estimated the risk of a mild exacerbation to be 38% lower in the single inhaler group and 35% lower in the separate inhaler group (p=0.011, versus budesonide). Severe asthma exacerbations occurred in eight (6.5%), 11 (9.6%) and 11 (8.9%) patients in the single inhaler, separate inhaler and the budesonide groups, respectively. Too few severe exacerbations occurred during the study to detect differences between treatments.
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). There was no statistically significant difference between groups regarding the FVC.
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). Respiratory infection was the most commonly reported adverse event. There were five serious adverse events: four (0.03%) in the single inhaler therapy group and one (0.01%) in the budesonide alone group. None was considered to be related to treatment. The five serious adverse events were one death by suicide and four hospitalizations (due to pneumonia, liver cysts, ischaemic stroke and intervertebral disc prolapse).
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Discussion |
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Although the patient population selected for enrolment in the study were treated with a mean inhaled steroid dose of 950 µg daily and had a mean baseline FEV1 of 73.8% of pred normal, baseline total asthma symptom scores were low and comparable between the three treatment groups. However, in spite of the low levels of symptoms reported, treatment with both single inhaler therapy and with budesonide plus formoterol in separate inhalers increased the percentage of asthma control days by 15% compared with budesonide alone. In effect, this implies that asthma patients treated with the single inhaler would have up to two additional months of asthma control per year. The improved asthma control was also exemplified by a 38% reduction in the risk of a mild asthma exacerbation in the single inhaler group and a 35% reduction in the separate inhaler group.
Asthma control in terms of managing exacerbations as well as treating the underlying pathophysiology of the disease, the inflammation, in the context of current treatment guidelines 1–3 is paramount. Success in gaining and maintaining control relies to a large extent on the patients or caregivers themselves in terms of participation in the management of their condition and adhering to the medication regimen. It has previously been reported that patient adherence to treatment decreases with increased complexity of treatment 12, including increased frequency of dosing and inhaler number 13, 14. Although this double-blind, double-dummy study was not designed to investigate adherence to treatment, simplifying asthma treatment by providing a single inhaler containing both formoterol and budesonide should lead to better asthma control and is an outcome measure that should be investigated in future clinical trials.
The benefits of combining treatments are directly related to the properties of the monoproducts. Budesonide has been used effectively to control asthma in a wide range of patients, including children 15. Formoterol has been shown to quickly gain control of asthma symptoms and then maintain that control over the course of a day or night 16. Patients may feel an immediate effect; thus, it may be speculated that adherence to maintenance treatment with single inhaler therapy will be improved over treatment with separate inhalers. This means that it is unlikely that patients will use ß2-agonist treatment at the expense of glucocorticosteroids, which are crucial for inflammatory control. Furthermore, the use of inhaled budesonide together with formoterol may have some synergistic effects on efficacy 9, 17, 18. In the present study, there was a tendency towards more rapid improvements in morning and evening PEF, and asthma symptom score with single inhaler therapy compared with separate inhaler therapy. The consistency of the effect of a more rapid improvement with the single inhaler versus separate inhalers was also reflected in the exacerbation profile (fig. 3). Consequently, a more rapid improvement in asthma control with the single inhaler versus separate inhalers and the possibility of a synergistic effect between budesonide and formoterol when administered via a single inhaler cannot be excluded, even though the differences between combination treatments in this study were small and not statistically significant. The present findings highlight the need for further studies in this area.
In summary, this study shows that budesonide/formoterol single inhaler therapy gives better asthma control than budesonide alone, in patients not previously fully controlled by glucocorticosteroids alone. The full potential of this new, single inhaler therapy has yet to be explored. Future directions for research may include the possibility of synergy between budesonide and formoterol.
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) or budesonide alone (------).
