Abstract
Systemic corticosteroids and additional short-acting ββ2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting ββ2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV1), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV1 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 μg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (−57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (−16 %; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.
INTRODUCTION
Exacerbations of COPD are traditionally treated with systemic corticosteroids and short-acting bronchodilators, and with antibiotics in case a bacterial airway infection is suspected or very severe airways obstruction is present. The effectiveness of systemic steroids, though used for decades, has only recently become “evidence based” (Citation[1], Citation[2]). A theoretically alternative treatment of COPD exacerbations, avoiding the use of systemic corticosteroids, is treatment with inhaled corticosteroids (Citation[3]). Additionally, immediate bronchodilation can also be obtained with the long-acting β 2-agonist formoterol due to its fast onset of action. This is an attractive option, since patients who already use combined inhaled corticosteroids and long-acting β 2-agonists as maintenance therapy, such as budesonide/formoterol could increase their daily dose when they are experiencing early signs of an exacerbation, thereby possibly preventing a full blown exacerbation. Such a treatment approach has been shown to be effective in the treatment of asthma (Citation[4]). Thus far it has not been tested in a randomised controlled trial in COPD exacerbations. The combination has proven efficacy in preventing exacerbations of COPD (Citation[5], Citation[6]).
Steroids are thought to exert their beneficial effect on exacerbations of COPD through their anti-inflammatory properties. Effects of systemic steroids on inflammation during exacerbations have not been reported, although some studies document changes in stable phase COPD (Citation[7], Citation[8]), effects that are also observed with inhaled steroids (Citation[9], Citation[10], Citation[11], Citation[12]). Effects of β 2-agonists depend largely on their bronchodilating properties. There are no data of anti-inflammatory effects of β 2-agonists in COPD, but in asthma anti-inflammatory properties have been described (Citation[13], Citation[14]). Although inflammation assessed in sputum in stable phase of COPD is mainly of neutrophilic origin, several studies have indicated that sputum eosinophils are increased during COPD exacerbations (Citation[15], Citation[16]). Furthermore sputum eosinophilia predicts a better response to a short-term steroid treatment in a stable phase of COPD (Citation[17], Citation[18], Citation[19]). We hypothesised that the clinical response to steroids in COPD exacerbations is due to the suppressive effect on the eosinophilic inflammatory component and therefore designated this cell as the primary efficacy endpoint to assess inflammatory treatment effects.
We examined whether a combination therapy with an inhaled corticosteroid and long-acting β 2-agonist, i.e. budesonide and formoterol (B/F), as available in a single inhaler would reduce inflammation and especially the eosinophilic component occurring during exacerbations, more effectively than placebo (PLAC). We estimated that documentation of effects on clinical parameters would require more patients and therefore pre-defined these parameters as secondary outcomes. For comparison, a third arm in the study received an oral corticosteroid.
Some of the results of this study have been previously reported in the form of an abstract (Citation[20], Citation[21]).
METHODS
Subjects
Inclusion criteria for the study at the start of the run in phase were: diagnosis of COPD, age > 40 years, postbronchodilator FEV1 < 85% predicted but > 0.7 liters, and an abnormal postbronchodilator FEV1/slow inspiratory vital capacity (VC) (< 88% predicted in men and < 89% predicted in women) (Citation[22]). Patients were not allowed to use oral corticosteroids, oxygen therapy, beta-blockers, or long-acting anticholinergics. All other bronchodilators were allowed. Asthma was excluded from a known diagnosis or a history suspicious for asthma. Patients had no significant other disease that could influence the results of the study. The study was performed in accordance with the principles stated in the Declaration of Helsinki. The local medical ethics committee approved the study. Written informed consent was obtained from all patients.
Study design
We recruited a cohort of COPD patients that was followed until the development of an exacerbation. Thereafter patients were randomized to three treatment regimens (). At inclusion, inhaled corticosteroids were discontinued, if used. After this visit, the subjects had to be stable during the run-in period, lasting 2 months. After the run-in period, spirometry was performed followed by a sputum induction procedure, and hereafter also long-acting β 2-agonists were withdrawn. From this day on, patients from this cohort contacted the research facility as soon as they experienced an exacerbation, as defined according to Davies (Citation[23]): a history of increased breathlessness and at least two of the following symptoms for ≥ 24 hours: increased cough frequency or severity, sputum volume or purulence, and wheeze. When presenting with an exacerbation, and provided that postbronchodilator FEV1 < 70 % predicted and PaO2 > 8.0 kPa, patients were randomised to a):160 μ g budesonide/4.5 μ g formoterol (Symbicort Turbuhaler®, AstraZeneca Sweden), 2 inhalations q.i.d. and placebo tablets, b): 30 mg prednisolone (AstraZeneca) as 6 tablets of 5 mg once daily and placebo inhalations, or c): placebo tablets and inhalations, in a double dummy set-up, for 14 days. Inhalation technique was practised at enrolment and at randomisation until satisfactory. All patients received a standard dose of an antibiotic (doxycyclin), and inhaled terbutaline and ipratropium bromide as needed. For the allocation to randomised treatment we used sputum eosinophils (< or ≥ 3%), FEV1 at exacerbation (< or ≥ 50% of predicted), smoking status (current or ex), inhaled corticosteroid and N-acetyl-cysteine use at start of study as stratification factors in a minimization process (see supplement for details on randomisation process).
Figure 1 Study design
Measurements
At randomization, and at day 3, 7, and 14, induced sputum, blood, and urine were collected, an electrocardiogram was made and heart rate, weight, blood pressure, and lung function were measured. Patients recorded morning and evening symptoms of breathlessness, sputum, and cough daily in a diary in the last 2 weeks of the run-in period and during the 2 weeks after randomisation (Citation[24]). Patients completed the Clinical COPD Questionnaire (CCQ) at each visit, and the Clinical Respiratory Questionnaire at baseline and at the and of treatment (Citation[25]). FEV1, VC, forced vital capacity (FVC), and specific airways conductance (sGaw) (Masterscreen Bodybox, Jäeger, Würzburg, Germany) were measured according to guidelines of the European Respiratory Society (Citation[22]). At 2 weeks and at 3 months after randomisation two follow-up visits were performed by phone in order to identify post-study treatment failures (systemic corticosteroid treatment within 2 weeks) or relapse (systemic corticosteroid treatment from 2 weeks to 3 months).
Sputum induction and processing
Sputum was induced by standard methods (Citation[26]), with modifications according to Pizzichini when the FEV1 was < 1.5 liters (Citation[27]). Messenger Ribonucleic Acid (mRNA) processing by real-time polymerase chain reaction and other methods are described in the online supplement.
Statistical analysis
The primary endpoint was the change in % sputum eosinophils defined as the ratio of the % eosinophils at day 14 to the % eosinophils of the randomisation visit (day 1). Using GAUSS from Aptech systems inc. (kernel revision 6.0.48), ratios were compared in a multiplicative analysis of variances model with the value of the randomisation visit included as a covariate. Pairwise treatment ratios and 95% confidence intervals were compared in the model using contrast. Secondary endpoints were analysed using similar methods. Power calculation was based on the change in eosinophils by steroid treatment in stable COPD in a previous study, demonstrating a change in eosinophils of 1.5% (see supplement). The primary comparison was that between budesonide/formoterol and placebo. No multiplicity adjustment has been performed for secondary variables.
RESULTS
Subjects
In the study 114 patients were included. During the observation period after the run-in period 45 patients reported an exacerbation and were randomised (). The other patients did not report an exacerbation in the observation period (n = 26), were excluded due to adverse events prior to being randomised (n = 13), or were excluded for other reasons. One patient died from a pulmonary carcinoma prior to being randomized. The characteristics of the randomised patients at baseline and at the start of their exacerbation are presented in .
Figure 2 B/F = Budesonide/Formoterol; PRED = Prednisolone; PLAC = Placebo.
Table 1 Patient characteristics
Two patients were withdrawn due to treatment failure (1 in the placebo group after 1 day and 1 in the B/F group after 7 days of treatment). The other 43 patients all completed the 2 weeks of randomised double-blind treatment.
Inflammatory cells
Treatment with B/F and PRED elicited a significant decrease versus placebo in the percentage sputum eosinophils (): the mean reduction after 2 weeks was 57% for B/F compared to an increase with 24% for placebo (p = 0.01) and a reduction of 58% for PRED (p = 0.007 versus placebo). No difference between the two active treatments was found, nor were there any significant differences in the other sputum cell differential counts or in the total cell counts between the treatment groups (). Blood eosinophil counts were not affected by either of the two active treatments. PRED treatment resulted in an increase in blood leucocyte count (mean change 3.1 × 109/L and blood neutrophils (mean change 1.91 × 109/L) which was significantly different from PLAC (p < 0.001 and p = 0.01 respectively).
Figure 3 * On day 3, 7, and 14, the ratio of sputum eosinophil % of the visit under study to the eosinophil% at randomisation are presented. The difference in ratios from start to end of treatment are significant for budesonide/formoterol versus placebo (p = 0.01) and for prednisolone versus placebo (p = 0.007). Data is expressed as geometric means and standard error of the mean. P-values for comparisons of these ratios at day 14 under budesonide/formoterol (320/9 μ g 4 times daily) versus prednisolone (30 mg once daily) and placebo.
Table 2 Sputum cells
Sputum mRNA
The Ct-values of the mRNA expression are shown in . B/F treatment resulted in a significantly larger decrease in interleukin-5 (IL-5) expression compared to placebo (p = 0.02). PRED treatment resulted in a smaller increase in expression of heme oxygenase-1 (HO-1) compared to B/F (p = 0.02) and in a smaller increase in the expression of transforming growth factor-ß (TGF-ß) mRNA compared to PLAC (p = 0.045).
Table 3 mRNA expression of sputum cells
Lung function
The change in FEV1 is shown in . FEV1 improved during the treatment period in all three groups. The increase in FEV1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). With PRED the FEV1 improved 27 ml (p = 0.71versus placebo). There were no significant differences in the effects of B/F or prednisolone versus placebo after 2 weeks on other lung function parameters ().
Figure 4 *On day 3, 7, and 14, the ratio of FEV1 of the visit under study to the FEV1 at randomisation are presented. Data is expressed as geometric means and standard error of the mean. P-values for comparisons of these ratios at day 14 under budesonide/formoterol (320/9 μ g 4 times daily) versus prednisolone (30 mg once daily) and placebo.
Table 4 Lung function parameters
Symptoms and health status
During both B/F and PRED treatment, significantly lower total symptom scores in the diaries were observed compared to the treatment with PLAC (mean difference −1.37 and −1.03 respectively; p < 0.01, p = 0.048). B/F treatment resulted also in lower cough symptom score compared to PLAC (mean difference −0.62, p = 0.015). There were trends towards lower sputum production scores under both B/F and PRED compared to PLAC (mean differences −0.38 and −0.39 respectively, p = 0.066 and p = 0.058).
The overall health status as measured by the CCQ did not differ significantly between B/F and PLAC (mean change 1.0 and 0.5 points, respectively: p = 0.08) (). However, the improvement in overall health status with B/F was significantly greater compared to that with PRED (mean change 0.4 points, p = 0.02). The minimal clinical important difference of the CCQ is a change of 0.4 points (28). The health status measured by the CRQ showed similar results (mean change B/F 0.47 and placebo 0.004, p = 0.07; mean change PRED –0.06, p = 0.04 versus B/F). After completion of randomized treatment, 18 patients had a treatment failure (in the first 2 weeks after completion) or a relapse (from 2 weeks to 3 months) : 7 under B/F, 7 under PRED, 4 under PLAC treatment.
Figure 5 *On day 3, 7, and 14, the difference of CCQ-score of the visit under study from the CCQ-score at randomisation are presented. The difference in means from start to end of treatment are significant for budesonide/formoterol versus prednisolone (p = 0.02) Data is expressed as means and standard error of the mean. P-values for comparisons of the arithmetic mean changes at day 14 under budesonide/formoterol (320/9 μ g 4 times daily) versus prednisolone (30 mg once daily) and placebo.
Adverse events and safety
No serious adverse events occurred during 14 days of study treatment. One serious adverse event (operation for a sinus maxillaris cyst) was reported during the three months follow-up period. No hospitalisations for respiratory symptoms were required. Furthermore there were no different patterns between the treatment groups in adverse events, characteristics on electrocardiograms, or blood pressure and heart rate, though under PRED treatment QRS duration decreased compared to PLAC (−2.7 ms versus +3.6 ms, p = 0.0048). B/F treatment did not significantly suppress serum cortisol compared to placebo (mean 16% lower p = 0.50). By contrast, the PRED treatment did suppress serum cortisol levels significantly versus placebo (mean 45% lower; p = 0.03). There were no significant differences in the changes in the serum glucose levels between the groups. The decrease in serum potassium under PRED (−0.29 mmol/L) differed significantly form the increase under PLAC (+0.03 mmol/L, p = 0.03).
DISCUSSION
Treatment of COPD exacerbations with high dose budesonide/formoterol (B/F) significantly reduced sputum eosinophils compared to placebo. This reduction in airway inflammation was accompanied by an improvement in symptoms. Prednisolone (PRED) treatment also reduced airway inflammation and symptoms. In contrast to B/F, PRED significantly suppressed plasma cortisol levels.
Several studies have reported that eosinophils increase during COPD exacerbations, both in airway biopsies and in induced sputum (Citation[15], Citation[16], Citation[29]). Although the effects of steroids (inhaled or oral) on inflammation during exacerbations had not been previously studied, several studies have assessed the effects of corticosteroids on inflammation in stable COPD. Gan et al. performed a meta-analysis of the effects of inhaled steroids in the stable phase of COPD, showing a trend towards reducing eosinophil counts in sputum of stable COPD patients. (Citation[30]) In a recent study, treatment of stable COPD with inhaled salmeterol/ fluticasone propionate also reduced sputum eosinophil counts (Citation[31]).
To evaluate the potential effects of corticosteroids on airway inflammation, we measured the sputum cell mRNA expression of several cytokines that play a role in the attraction/survival of eosinophils, our primary endpoint, or may contribute to the induction and resolution of COPD exacerbations. We found a larger decrease in IL-5 expression with B/F compared to placebo. Since IL-5 is involved in eosinophil growth and differentiation, this reduction fits well with the reduction in sputum eosinophils (Citation[32]). Under placebo treatment a larger increase from day 1 to day 14 was observed in expression of TGF-β compared to PRED and similar trends, though not significant, compared to B/F. This increase under placebo may signify an increased inflammation and tissue damage due to the lack of anti-inflammatory treatment. We do not have an explanation for the smaller increase in HO-1 expression under PRED compared to B/F. We would have expected a decreased expression by both the active treatments, since HO-1 is a stress inducible enzyme, and we would have expected a decrease in stress stimuli by treatment due to a reduction in inflammation. Perhaps this effect has been confounded by other stress factors such as smoking.
The beneficial effects of steroid treatment on parameters of inflammation were accompanied by improvements in clinical symptoms. The total symptom scores as recorded in the diaries were better under both B/F and the PRED treatment, with a significant improvement in cough for B/F and trends in improvement in sputum production under both B/F and PRED treatment.
This study is the first to use an airway inflammatory parameter as the major endpoint for treatment efficacy in exacerbations of COPD. A few randomised controlled trials used clinical endpoints to asses the effects of oral prednisolone on COPD exacerbations in hospitalized patients and outpatients (Citation[1], Citation[2], Citation[33], Citation[34]), and a meta-analysis concluded that it reduced treatment failure and the need for additional treatment, and increased the rate of improvement in lung function and dyspnea over the first 72 hours (Citation[35]).
Maltais et al showed beneficial effects of inhaled budesonide (Citation[3]), comparing 2 mg nebulised budesonide every 6 hours and 30 mg oral prednisolone every 12 hours, and both treatments improved airflow limitation when compared with placebo. Although we did not show a statistically significant effect on airflow limitation between the three groups in our study, a trend was found in the comparison between B/F and PLAC (see , p = 0.07). The lack of significance is likely due to the smaller patient numbers in our study (45 versus 199) since the magnitude of improvement in FEV1 was similar (125 ml versus 100 ml). Our study sample size was based on power calculations with changes in eosinophil percentage as primary end point. Another difference between the studies is the time point of evaluation, i.e. in our study at 2 weeks after randomisation, versus 72 hours in Maltais' study.
A great advantage of B/F therapy above PRED should be the avoidance, or at least a reduction, of systemic side effects. Several studies have shown that inhaled corticosteroids have fewer side effects compared to oral corticosteroids. Morice et al investigated the side effects of nebulised budesonide (2 mg twice daily) with oral prednisolone (30 mg at once daily) in the treatment of COPD-exacerbations. They found that prednisolone treatment resulted in lower urinary corticosteroid metabolites, and lower serum osteocalcin than inhaled treatment (Citation[36]). In our study we investigated serum cortisol levels. We found that there was no significant suppression of serum cortisol by B/F treatment compared to placebo. PRED treatment did suppress serum cortisol levels as expected and this aspect favours the treatment with B/F over prednisolone.
Our study was not powered to assess equality of clinical effects of the two active treatment arms. Such a non-inferiority trial would require more patients. Any lack of difference in statistical terms between B/F and PRED in the present study could therefore be due to a type 2 error and should not be interpreted to signify equal or similar effects. Nevertheless, since all parameters favoured B/F over PRED, there was no indication of inferiority of B/F versus prednisolone in this setting.
The use of B/F for the treatment of mild to moderate exacerbations of COPD at home improved both inflammation and symptoms and was well tolerated. Whether B/F treatment is as effective as PRED and is to be favoured B/F over PRED because of fewer side effects, will require larger-scale efficacy studies. An interesting option is the possibility to treat exacerbations at home in an earlier stage of an evolving exacerbation by B/F, as was recently demonstrated to be effective in the treatment of asthma (Citation[4]). Whether this earlier institution of effective therapy could also prevent in COPD the development of full-blown exacerbations and thereby hospitalisations is an interesting option that should be studied in future studies.
We conclude that sputum eosinophils and symptoms of patients with mild to moderate COPD exacerbations can be improved by a 2-week treatment with 160 μ g budesonide/ 4.5 μ g formoterol, 2 doses q.i.d., compared to placebo. A next study should aim to establish whether treatment of exacerbations at home with budesonide/formoterol can replace traditional treatment with oral corticosteroids.
EFFECTS OF COMBINED BUDESONIDE AND FORMOTEROL TREATMENT IN OUT-PATIENT COPD EXACERBATIONS
D. Bathoorn1, J.J.W. Liesker1, D.S. Postma1, M. Boorsma2, E. Bondesson3, G.H. Koëter1, H.F. Kauffman4, A.J.M. van Oosterhout4 and H.A.M. Kerstjens1. Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pulmonology1 and Laboratory of Pulmonology and Allergology4, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, and AstraZeneca R&D, Zoetermeer, The Netherlands2 AstraZeneca R&D, Lund, Sweden3.
SUPPLEMENT
Determination of sample size
The power calculation was performed on the primary parameter: sputum eosinophils as change from day 1 to day 14 in the study. Limited data was available on the course of the disease as assessed by inflammatory parameters. A study in stable disease and using a cross over design in 19 patients could demonstrate a 1.5% decrease in sputum eosinophils. (Citation[1]) In the present study the patients served as their own controls during the study, the changes within groups were compared between groups. With 20 patients per group it was expected that the improvement in symptoms and lung function parameters were not statistically significant different.
Method of assigning patients to treatment groups
After fulfilling all inclusion criteria and none of the exclusion criteria, the patients were assigned blindly to one of the three treatments groups by minimization. The following factors were assumed to be of importance for the treatment outcome and were therefore be used in the stratification process. Treatment to the first patient was fully random. Allocation of subsequent patients was influenced by former allocations but still had a component of randomness. In this way, the marginal treatment totals were balanced for each level of each patient factor. Sputum eosinophils was given double importance:
Sputum eosinophils, based on a preliminary analysis at the exacerbation visit (< 3% vs ≥ 3%)
Current versus ex-smoker (stopped > 6 months prior to enrolment)
N-acetyl-cysteine used as maintenance treatment in the last year before enrolment (yes versus no)
Inhaled steroid maintenance treatment in the last year prior enrolment (yes versus no)
FEV1 at exacerbation (< 50 % versus ≥ 50% of predicted).
The actual distribution of the stratification factors over the three treatments is given in the Table below:
Sputum induction and processing
Sputum was induced by standard methods but with modifications according to Hargreave when the FEV1was below 1.5 liters (). Whole sputum samples were processed using dithiotreitol within 120 minutes as described before (Citation[2]) Cytospins were prepared and cell-free supernatant was collected and stored in aliquots at −80°C pending analyses of soluble mediators.
Figure E1
Differential cell counts were counted on May Grünwald Giemsa stained cytospins in a blinded fashion. (Citation[3]) Cell counts were expressed as percentage of 2 × 300 non-squamous cells. A sputum sample was considered inadequate when the percentage squamous cells was > 80%. The safety of this procedure in the patients in the present study was previously described. (Citation[4])
Sputum cytokine mRNA expression
Messenger Ribonucleic Acid (mRNA) was harvested from cells in a whole sputum sample, containing amongst others 1 million living non-squamous sputum cells. RNA was isolated using a RNeasy Mini Kit (Qiagen, Venlo, The Netherlands) and cDNA was synthesized as described before. (Citation[5]) Expression of cytokine mRNA was analysed by quantitative real-time PCR, using the ABI 7900 HT system (Applied Biosystems, Nieuwekerk a/d IJssel, The Netherlands). The gene expression assays for HO-1, tumor necrosis factor-α (TNF-α), chemotactic cytokine-L5 (CCL5), Interleukin (IL)-5, Interleukin (IL)-10, Interleukin (IL)-12, Interleukin (IL)-13, TGF-β, interferon-γ (IFN-γ), and β -2-microglobulin, were obtained from Applied Biosystems (Nieuwekerk a/d IJssel, Netherlands). Cytokine gene expression was normalised to expression of β -2-microglobulin. The mRNA quantification is expressed in threshold cycle values (Ct-values), which is the number of amplification cycles to reach a detectable mRNA amount. Thus lower Ct-values correspond with higher mRNA expression.
Serum cortisol analysis
Serum cortisol was measured by radioimmunoassay (RIA) after prior extraction with dichloromethane and HPLC purification, with initial 3H-cortisol addition as a recovery tracer. The mobile phase consisted of 14% isopropanol, 0.10% trifluoroacetic acid in water, run on a Hypersil Gold column. The fractions containing cortisol were identified by liquid scintillation counting of 50 μ l aliquots, evaporated to dryness and dissolved in assay buffer. The RIA was based on an antiserum raised in sheep against a 21-hemisuccinate-BSA conjugate, 3H-cortisol as tracer with dextrane-coated charcoal for separation between free and antibody-bound 3H activity. Calculation of results included corrections for the contribution of mass and radioactivity from the recovery tracer. The detection limit was 0.012 μ mol/l. At a level of 0.299 μ mol/l the between-run CV was 10.9%. Addition of budesonide up to 3.88 μ mol/l and prednisolone up to 4.62 μ mol/l did not produce any detectable response.
Acknowledgements
The authors thank Ibolya Sloots, Brigitte Dijkhuizen, Koos van de Belt, and Janneke Heimweg for all sputum measurements, Marco van der Toorn for the mRNA measurements, the lung function department for the many lung function measurements, and Alec Ross for the cortisol measurements (UMC St. Radboud, Nijmegen).
The study was performed at the Department of Pulmonology, University Medical Center Groningen, University of Groningen, the Netherlands. This study was supported by an unrestricted research grant from AstraZeneca, the Netherlands. Martin Boorsma and Eva Bondesson are employed by AstraZeneca. Erik Bathoorn's and Jeroen Liesker's salaries during the conduct of the study were paid by AstraZeneca. This study has been registered at http://www.clinicaltrials.gov, ID: NCT00239278.
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