Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma

Study subjects

Patients with asthma aged ≥12 yrs were recruited from multiple clinical practices across Canada. Inclusion criteria comprised: asthma diagnosis for ≥3 months (using the American Thoracic Society definition 13); use of ≥400 μg ICS daily; and either daily treatment with ICS alone and a history of suboptimal asthma control in the month before enrolment with ≥3 inhalations of as-needed rescue for symptom relief during the 7 days prior to enrolment, or daily maintenance treatment with both ICS and LABA.

Exclusion criteria included: previous treatment with budesonide/formoterol as both maintenance and reliever therapy; use of any β-blocking agent; use of oral corticosteroids as maintenance treatment; asthma exacerbations requiring change in asthma treatment during the previous 14 days; planned hospitalisation during the study; a smoking history >10 pack-yrs; pregnancy; breastfeeding or planned pregnancy; and any other significant disease that, in the opinion of the investigator, may put the patient at risk due to their participation in the study. The study was approved by research ethics committees in the multiple institutions involved and performed in accordance with the Declaration of Helsinki, International Conference on Harmonization/Good Clinical Practice and the AstraZeneca policy on bioethics. Written informed consent was obtained from each patient.

Study design

This randomised, open-label, parallel-group, multicentre study (study code D5890L00004) aimed to reflect ordinary clinical practice (fig. 1⇓). An open design was necessary, first, to allow multiple treatment options in the comparator arm and, secondly, to implement the essential part of the new strategy, namely the use of budesonide/formoterol for both maintenance and as-needed use. Following a 2-week run-in period maintaining their usual asthma therapies, patients were randomised to budesonide/formoterol maintenance and reliever therapy or to CBP. The budesonide/formoterol dosage was 160/4.5 μg delivered dose, one inhalation twice daily (b.i.d.) plus additional doses as needed, up to a total of 12 inhalations daily. Patients allocated to this arm were instructed in the correct use of the Turbuhaler® (Symbicort Turbuhaler®; AstraZeneca) at randomisation. CBP was determined according to the investigators' judgement following the Canadian Asthma Consensus Guidelines 2 and could involve any therapy including either ICS/LABA combination product but not use of budesonide/formoterol as both maintenance and reliever therapy. Patients were evaluated at 4, 13 and 26 weeks after randomisation. This study is a registered clinical trial at the ClinicalTrials.gov website (identifier: NCT00238784) .

Outcomes

The primary outcome was time to first severe asthma exacerbation, defined as hospitalisation or emergency room (ER) visit and/or use of oral corticosteroid for ≥3 days due to asthma. Secondary outcomes included the number of severe exacerbations, mean use of as-needed medication (recorded for 2 weeks before each visit), prescribed asthma medications, peak expiratory flow (PEF), Asthma Control Questionnaire (five-item version; ACQ-5) score 14, health economics and safety. In a subgroup of the present study, the primary outcome was the change in induced sputum eosinophil count.

Methods

A notebook was used to record exacerbations, changes in prescribed asthma medications and adverse events at any time, and use of reliever medication on each of the 14 days preceding the study visit. The notebook was reviewed by the investigator at visits 2–5.

Start and end dates for exacerbations were defined as the first and last day of hospitalisation/ER treatment, or the first and last day of prescribed oral corticosteroid treatment, respectively. If an exacerbation included both hospitalisation/ER treatment and oral corticosteroid treatment, the start and end dates were the first and last day that either criterion was fulfilled.

PEF measurements were performed by each patient at visits 1 and 5, using the same PEF meter at both visits.

The ACQ-5 14 was self-administered during visits 2–5. All questions were assessed on a seven-point scale from 0 (good control) to 6 (poor control). The overall score was the mean of the five responses. Answers to four of the five questions were required to provide a value. Change in ACQ-5 score from visit 2 to the average during treatment (visits 3–5) was calculated.

Assessment of safety included reporting of common adverse events, serious adverse events (asthma and nonasthma related) and discontinuation of study treatment due to adverse events (asthma and nonasthma related).

In patients from five academic centres, sputum inductions were undertaken at visits 2 and 5, and sputum eosinophil counts were measured using standardised methods 15. Treating physicians were blinded to results of sputum analyses so that treatment was not influenced by these measurements.

The health economic evaluation was conducted from the societal perspective, including direct and indirect costs. Direct costs included: study or prescribed medications; rescue medications; additional asthma medications taken during exacerbations; visits to family physicians, specialists or healthcare professionals; expenses, such as parking and public transportation for such visits; diagnostic tests; home visits; ambulance use; ER visits; and hospitalisations. Indirect costs included: number of days the patient missed work or school; number of days that caregivers were absent from work due to patient's asthma; and total out-of-pocket expenses. The asthma medication cost per patient for the budesonide/formoterol maintenance and reliever therapy arm was calculated as follows:

Maintenance dose cost (2 × unit price × days in study) + as-needed dose cost (average daily inhalation × unit price × days in study) + cost of exacerbation treatments (if applicable) + dispensing fee

In the CBP arm, cost was calculated as follows:

(unit price of all maintenance therapy × days used) + as-needed dose cost (average daily inhalation × unit price × days in the study) + cost of exacerbation treatments (if applicable) + dispensing fee

Costs were adjusted to an annual rate.

Analysis

All analyses were undertaken using the intention-to-treat approach. Time to first severe exacerbation was determined using Kaplan–Meier curves and compared between treatments with a log-rank test. The treatment difference was estimated by the Cox proportional hazards model with treatment as a factor. The number of severe asthma exacerbations per patient was compared between treatment groups using a Poisson regression model with treatment as a factor and time in study as an offset variable. The use of as-needed medication, changes in PEF from baseline to visit 5 and changes in ACQ-5 score (visits 3–5) from baseline were compared between treatments using ANOVA with treatment as a factor and baseline mean as a covariate. The mean use of ICS was compared between treatments using ANOVA. The annual asthma medication costs and annual total costs were compared between treatments using the bootstrapping method. A p-value <0.05 was considered statistically significant. Adverse events were analysed using descriptive statistics.

For the airway inflammation sub-study, a multiplicative ANOVA (i.e. log transformation) was used to compare the percentage change in eosinophil count in induced sputum from baseline to the end of treatment. To facilitate the log transformation, sputum eosinophil counts of 0% were assigned a value of 0.125% (half of the lowest nonzero value).

Using assumptions, based on previous studies, that 13% of patients would experience a severe exacerbation in one group and 8.2% in the other group, this difference would be detected with 80% probability at a 5% level of significance if the study included 650 patients per group. In order to compensate for an estimated dropout rate of 15% through run-in, a sample size of 1,530 patients was determined. The sample size for the airway inflammation subgroup analysis was calculated based on the log scale of the data. A sample size of 45 per group (90 subjects in total) would be able to detect a 40% difference (approximately equivalent to a treatment difference of -0.518 in log scale) between the two treatments with a power of 80% and a significance level of 5%. To compensate for dropouts, 110 enrolled subjects (or 105 randomised subjects) were recruited.

Study subjects

The number of patients enrolled, randomised and completing the study, including the airway inflammation sub-study, is shown in table 1⇓. The treatment groups were comparable with respect to demographic and baseline data (table 2⇓). The characteristics of the 115 patients enrolled who participated in the airway inflammation sub-study, and of the 88 patients completing the sub-study with sputum measurements at both time-points, did not differ from the full study population (please refer to supplementary table E1 and fig. E1).

Asthma severity at baseline (assessed by ICS dose, asthma symptoms and lung function) was classified as mild-persistent in 18%, moderate-persistent in 43% and severe-persistent in 39% of patients, based on a modification of the Global Initiative for Asthma guidelines 1. Prior to randomisation, ∼66% of patients were prescribed an ICS/LABA combination, with similar use of fluticasone/salmeterol and budesonide/formoterol between groups, and ∼10% in each arm were prescribed leukotriene receptor antagonists (LTRA).

Time to first severe exacerbation

The primary efficacy variable, time to first severe exacerbation, is shown in figure 2⇓. There was no significant difference between the two treatments (Cox hazard ratio 0.99, 95% confidence interval (CI) 0.70–1.41; p = 0.95, log-rank test).

Number of severe exacerbations

The incidence of severe exacerbations, in total and by subtype, is shown in table 3⇓. In total, 61 (7.9%) subjects on budesonide/formoterol maintenance and reliever therapy reported 69 severe exacerbations, while 63 (8.2%) subjects on CBP reported 77 severe exacerbations. Using Poisson regression, the mean number of severe exacerbations per patient per year was 0.19 versus 0.21 (ratio 0.92, 95% CI 0.67–1.28; p = 0.63) for budesonide/formoterol maintenance and reliever therapy compared with CBP (table 3⇓).

Of those reporting severe asthma exacerbations based on oral corticosteroid use, no difference was seen in the number of patients with at least one event or the total number of events. Total days of oral corticosteroid use were, however, 17% lower with budesonide/formoterol maintenance and reliever therapy (590 days) compared with CBP (709 days; table 3⇑).

Of those reporting severe asthma exacerbations based on hospitalisation and/or ER visits, Poisson regression demonstrated a trend towards fewer such exacerbations per patient per year with budesonide/formoterol maintenance and reliever therapy: 0.04 versus 0.08 with CBP (ratio 0.59, 95% CI 0.32–1.09; p = 0.09; table 3⇑). The incidence of severe asthma exacerbations leading to hospitalisation and/or ER visit is shown in figure 3⇓.

As-needed reliever use

Mean as-needed reliever use decreased slightly, from 1.25 to 0.94 inhalations·day⁻¹ with budesonide/formoterol maintenance and reliever therapy and from 1.22 to 1.09 inhalations·day⁻¹ with CBP (table 4⇓), a 14% lower use with budesonide/formoterol maintenance and reliever therapy (p = 0.0036). A total of 15 (2%) subjects in the budesonide/formoterol maintenance and reliever therapy arm required more than eight as-needed inhalations on ≥1 day versus 30 (4%) subjects in the CBP arm (p = 0.028).

Prescribed asthma medications

Maintenance medication in the budesonide/formoterol maintenance and reliever therapy arm was fixed by protocol. In the CBP arm, ICS without LABA were prescribed in 18% and ICS with LABA in 82% of subjects: 44% used budesonide/formoterol, 32% fluticasone/salmeterol and 8% separate inhalers of ICS and LABA, with some overlap in these groups. LTRAs were prescribed in 11% of subjects, while more than three separate classes of controllers were used in 9% of CBP patients.

Inhaled corticosteroid doses

The mean (range) ICS dose (expressed as beclomethasone dipropionate equivalents 2) was 1,015 (30–4,000) µg·day⁻¹ in the CBP group and 748 µg·day⁻¹ (500 µg·day⁻¹ maintenance + 248 (range 0–2,710) µg·day⁻¹ as needed) in the budesonide/formoterol maintenance and reliever therapy group, a total reduction of 26% (267 µg·day⁻¹, 95% CI 226–307; p<0.0001).

Peak flow

PEF increased from 94.8 to 98.0% predicted with budesonide/formoterol maintenance and reliever therapy, and from 94.1 to 96.3% with CBP. No significant difference was found between treatment groups (p = 0.32).

Asthma Control Questionnaire

The ACQ-5 score decreased from 1.27 to 1.08 with budesonide/formoterol maintenance and reliever therapy and from 1.24 to 1.09 with CBP, representing an improvement in asthma control in both groups. No significant difference was found between the treatment groups (p = 0.46).

Sputum eosinophil counts

Of the 115 subjects randomised into the airway inflammation sub-study, 88 subjects produced sufficient sputum for analysis at visits 2 and 5. Mean eosinophil cell counts were within the range for controlled inflammation in both groups at baseline and at the end of the study. The geometric mean (range) sputum eosinophil count decreased in the budesonide/formoterol maintenance and reliever therapy group (from 0.99 (0.125–26.0) to 0.73 (0.125–19.75); p = 0.0502) and in the CBP group (from 1.22 (0.125–51.5) to 1.16 (0.125–57.5); p = 0.97; fig. 4⇓). No significant difference was found between the treatment groups for reduction in mean sputum eosinophil count (p = 0.193). The number of patients with eosinophil counts >2% at the beginning (14 out of 40 and 11 out of 48) and end (12 out of 40 and 13 out of 48) of study in CBP versus budesonide/formoterol maintenance and reliever therapy, respectively, were not significantly different.

Health economics

The asthma medication cost and the total cost per patient per year were 28 and 23% lower, respectively, with budesonide/formoterol maintenance and reliever therapy versus CBP. The between-group difference (95% CI) in asthma medication costs (Can$ -353.60 (-419.72– -293.27); \#8364;-240.83 (-285.87– -199.75)) and total cost (Can$ -315.55 (-420.50– -200.52); \#8364;-214.92 (-286.40– -136.57); Can$1 = \#8364;0.6811, exchange rate of November 26, 2007) were statistically significant (both p<0.0001).

Safety

All treatments were well tolerated and no new safety concerns were identified. There were no clinically important differences between the treatment groups in the patterns of adverse events and serious adverse events (table 5⇓). Deterioration of asthma was only recorded as an adverse event if it was a serious adverse event or resulted in discontinuation of treatment. In total, 34 patients discontinued treatment due to adverse events (27 on budesonide/formoterol maintenance and reliever therapy and seven on CBP). Discontinuation due to asthma worsening or exacerbation was reported in 12 patients (nine on budesonide/formoterol maintenance and reliever therapy and three on CBP). The majority (85%) of those who discontinued therapy in the budesonide/formoterol maintenance and reliever arm had changed from metered-dose inhalers as their usual therapy to Turbuhaler® (AstraZeneca) delivery at randomisation. There were only four discontinuations on budesonide/formoterol maintenance and reliever therapy due to a severe exacerbation and three on CBP. Discontinuation due to serious adverse events occurred in six patients, three in each treatment group.

There were three deaths, one in the budesonide/formoterol maintenance and reliever therapy arm (due to injury) and two in the CBP arm (due to myocardial infarction and myopericarditis). Deaths were not considered by the investigators to be causally related to study treatment.