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1 bs_bs_banner ORIGINAL ARTICLE Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: Phase III study results TITO ATIENZA, 1 TERESITA AQUINO, 2 MARCELO FERNÁNDEZ, 3 WATCHARA BOONSAWAT, 4 MITSURU KAWAI, 5 TAKAHIDE KUDO, 6 JAN EKELUND, 7 STEFAN IVANOV 7 AND LARS-GORAN CARLSSON 7 1 Mary Mediatrix Medical Center, Lipa City, Batangas, 2 Veterans Memorial Medical Centre, Quezon City, Philippines, 3 Centro Respiratorio Quilmes, Buenos Aires, Argentina, 4 Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, 5 Kawai Chest Clinic, Kyoto, 6 AstraZeneca KK, Osaka, Japan, and 7 AstraZeneca R&D, Molndal, Sweden ABSTRACT Background and objective: To evaluate the efficacy and tolerability of budesonide/formoterol as maintenance and reliever therapy versus budesonide/ formoterol maintenance plus terbutaline in adults with persistent asthma not adequately controlled with inhaled corticosteroid (ICS) therapy alone. Methods: In this 12-month, randomized, doubleblind, parallel-group, phase III study (NCT ), patients (age 16 years; receiving maintenance ICS; 1 severe exacerbation in the 12 months prior to study entry) were randomized to either budesonide/ formoterol 160/4.5 mg 1 inhalation twice daily plus budesonide/formoterol 160/4.5 mg as-needed or budesonide/formoterol 160/4.5 mg 1 inhalation twice daily plus terbutaline 0.4 mg as-needed for 12 months. Primary outcome: time to first severe asthma exacerbation; secondary outcomes included: lung function, asthma symptom variables and tolerability. Results: Two thousand and ninety-one patients were randomized: 170 (16%) receiving budesonide/ formoterol maintenance and reliever therapy experienced 259 severe exacerbations versus 229 patients (22%) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations. Budesonide/formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation versus budesonide/formoterol plus terbutaline (P = ) and reduced the instantaneous risk of an exacerbation by 30% (hazard ratio 0.70, 95% confidence interval , P = ). Times to first oral Correspondence: Tito Atienza, Mary Mediatrix Medical Center, JP Laurel Highway, Lipa City, Batangas 4217, Philippines. drtito104@yahoo.com Conflict of Interest Statement: AstraZeneca contributed to the funding, design, analysis and writing of the study. T. Atienza and WB have been members of scientific advisory boards and received honoraria for lectures and research grants from Glaxo- SmithKline, AstraZeneca, Abott and Novartis. TK is employed by AstraZeneca KK in Japan, and JE, SI and LGC are employed by AstraZeneca R&D in Sweden. Received 9 May 2012; invited to revise 21 June 2012; revised 23 July 2012; accepted 15 August 2012 (Associate Editor: Paul Thomas). SUMMARY AT A GLANCE Budesonide/formoterol maintenance and reliever therapy provides better asthma control, as evidenced by prolonged time to first severe exacerbation, reduced risk of severe asthma exacerbations and improvements in lung function, than the same budesonide/formoterol maintenance treatment plus terbutaline as-needed in patients with asthma uncontrolled with ICS alone. steroid use, first hospitalization and first emergency room treatment were all significantly prolonged in the group versus budesonide/formoterol plus terbutaline. Both treatment groups were well tolerated. Conclusions: Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control, including a prolonged time to first severe asthma exacerbation, than budesonide/formoterol plus terbutaline and was well tolerated. Budesonide/ formoterol maintenance and reliever therapy also improved lung function and asthma symptoms. Key words: asthma, budesonide/formoterol, budesonide/ formoterol as maintenance and reliever therapy, exacerbation. Abbreviations: ACQ, asthma control questionnaire; FEV 1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid. INTRODUCTION Asthma treatment guidelines recommend maintenance therapy with a low-to-medium dose of inhaled corticosteroid (ICS) combined with a long-acting b 2-agonist, plus as-needed reliever therapy with a short-acting b 2-agonist, in patients with persistent asthma not adequately controlled by maintenance therapy with a low-to-moderate dose of ICS alone. 1 The addition of a long-acting b 2-agonist to an ICS as doi: /resp.12009
2 Budesonide/formoterol in asthma 355 maintenance therapy has been shown to be more effective than doubling the dosage of ICS alone. 2 5 Despite this, many patients continue to be symptomatic and experience asthma exacerbations, and while patients adjust their medication in an attempt to regain symptom control, they often do so inappropriately by increasing their reliever (short-acting b 2-agonist) medication. 6,7 Budesonide/formoterol maintenance and reliever therapy uses the same budesonide/formoterol inhaler for both maintenance and reliever therapies. Consequently, when patients seek relief from worsening asthma symptoms, they receive both a bronchodilator as well as an anti-inflammatory agent to address the underlying physiological factors driving the symptomatic worsening. The efficacy of inhaled budesonide/formoterol for both maintenance therapy and as-needed symptom relief has been demonstrated in six randomized, double-blind 8 13 and three randomized, non-blind, parallel-group, active-controlled asthma trials. This approach using the dry powder inhaler device is recommended in many countries but currently not in the US, in which the pressurized metered-dose inhaler is the only approved delivery device. 17 This study evaluated the time to first severe asthma exacerbation with budesonide/formoterol maintenance and reliever therapy versus budesonide/ formoterol maintenance plus terbutaline in an adult patient population (including Japanese patients) with persistent asthma not adequately controlled with ICS alone. METHODS This was a 12-month, randomized, double-blind, parallel-group, active-controlled, international phase III study (NCT ) in patients with symptomatic asthma not adequately controlled despite the use of ICS and was conducted in 148 centres across 13 countries. The protocol was approved by the Institutional Review Boards, and the study was performed in accordance with the ethical principles of the Declaration of Helsinki and the AstraZeneca policy on Bioethics and Human Biological Samples. All patients provided written informed consent prior to enrolment. Patient population Patients, age 16 years with a diagnosis of and 6 months documented history of persistent asthma, a prebronchodilator forced expiratory volume in 1 s (FEV 1) 50% of predicted normal, reversible airway obstruction (increase in FEV 1 12% relative to baseline), receiving maintenance ICS for 3 months before study entry and at a constant dose for 4 weeks before study entry, and having at least one asthma exacerbation in the 12 months prior to study entry, were eligible. To be randomized, patients had to have used their as-needed medication on at least 5 of the last 7 days of the run-in phase. During the run-in, patients were also required to be exacerbation-free, not to have required 10 as-needed inhalations on any 1 day and to have provided morning peak expiratory flow values for at least 8 of the last 10 days. Key exclusion criteria: a respiratory infection affecting asthma within 4 weeks of entry; requiring treatment with oral corticosteroids within 4 weeks of entry; current or previous smoker with a smoking history of 10 pack years; and any clinically relevant abnormal findings on physical examination or laboratory evaluation or any significant disease or disorder that could put the patient at risk or may influence the study results, as judged by the investigator. Study design and treatments Following a 2-week run-in period (patients used their ICS at the same dose as previous treatment and terbutaline as reliever medication), eligible patients were randomized to receive either budesonide/formoterol 160/4.5 mg 1 inhalation twice daily plus budesonide/ formoterol 160/4.5 mg as-needed or budesonide/ formoterol 160/4.5 mg 1 inhalation twice daily plus terbutaline 0.4 mg as needed for 12 months (Fig. 1). A maximum of 10 inhalations of as-needed medication were permitted each day. All drugs were delivered via identical Turbuhaler inhalers (AstraZeneca, Molndal, Sweden). Randomization was done in blocks, and the unique randomization code (assigned to each patient in a sequential order at each centre) was taken from a randomization list prepared from a computerized system at AstraZeneca by a person who was not otherwise involved in the study. The investigational product was double-blind to patients, study site personnel, pharmacy (if applicable) and AstraZeneca study teams. Identical Turbuhaler inhalers with identical labelling format were used maintain blinding. Study objectives and outcomes The primary objective was to compare the efficacy of therapy with budesonide/formoterol plus terbutaline as needed by evaluation of time to first asthma exacerbation. The primary outcome variable was the time to first severe asthma exacerbation, defined as deterioration in asthma leading to oral corticosteroid treatment for at least 3 days, or hospitalization or emergency room treatment due to asthma. Secondary outcome variables included morning and evening peak expiratory flow, FEV 1, use of as-needed medication, asthma symptom score, night-time awakening, symptom-free days, as-needed medication-free days, asthma control days, time to first mild asthma exacerbation, number of mild asthma exacerbation days and asthma control questionnaire (ACQ). Mild exacerbations were defined using diary data as morning peak expiratory flow that was below baseline by 20%, daily as-needed mediation use 2 inhalations above baseline or a night-time awakening due to asthma symptoms. Safety evaluations included adverse event reporting, monitoring of clinical laboratory variables, 12-lead electrocardiogram and vital signs.
3 356 T Atienza et al. Figure 1 Study design. *Patients were allowed to use up to 10 inhalations of the as-needed medication during one single day in addition to maintenance treatment. If a patient needed more as-needed medication in one single day, contacts had to be made with the investigator for reassessment of the patient s condition. Patients had to use the as-needed medication whenever they needed to relieve symptoms but not for prophylactic reasons. Statistical analysis Assuming, at the end of the study, that the proportion of patients experiencing an asthma exacerbation was 20% in the budesonide/formoterol plus terbutaline group and 14% in the budesonide/formoterol maintenance and reliever therapy group, a log-rank test (two-sided, significance level of 5%) could detect this difference with 90% probability if the study includes 827 patients per group. The incidences of asthma exacerbations values of 20% and 14% were based on experience from similar studies. 9,11 To compensate for a potential withdrawal rate of 10%, a total of 900 randomized patients per treatment group was aimed for. All hypothesis testing was conducted using twosided alternative with a significance level of 5%. The time to first severe asthma exacerbation was described using Kaplan Meier curves, and differences between treatment groups were evaluated using a log-rank test based on a Cox proportional hazards model. The total numbers of severe and mild asthma exacerbations were compared between groups using a Poisson regression model with treatment and country as factors and the time in study as an offset variable. The confidence limits and the P-value were adjusted for overdispersion. Change in FEV 1 was evaluated using a multiplicative analysis of covariance model with treatment and country as fixed factors and baseline FEV 1 as a covariate. Treatment differences were estimated from the model, and 95% CI was calculated. Changes in diary data were evaluated using the average values from the run-in period (average for the last 10 days) and the average values during the treatment period, and analysed using an additive analysis of covariance model with treatment and country as fixed factors and the run-in period average as a covariate. Comparison between treatment groups for change in ACQ score was performed in the same way as that for FEV 1. All safety variables are presented descriptively. RESULTS Two thousand and ninety-one patients were randomized to budesonide/formoterol maintenance and reliever therapy (n = 1049) or budesonide/formoterol plus terbutaline (n = 1042); of these, n = 956 and n = 932, respectively, completed the study (Table 1). The baseline demographics and disease characteristics are summarized in Table 2. Overall, the treatment groups were well matched. The mean age of the study population was 45.6 years, the median time since asthma diagnosis was 12 years, the median ICS dose at study entry was 640 mg, and the mean baseline FEV 1 was 69.9% of predicted normal. Severe exacerbations Overall, 170 patients (16%) receiving budesonide/ formoterol maintenance and reliever therapy experienced 259 severe exacerbations compared with 229 patients (22%) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations (Table 3). The use of oral steroids, number of emergency room treatment and hospitalizations were also lower among patients receiving budesonide/ formoterol maintenance and reliever therapy compared with those receiving budesonide/formoterol plus terbutaline. Budesonide/formoterol maintenance and reliever therapy statistically significantly prolonged the time to first severe exacerbation compared with budesonide/formoterol plus terbutaline (P = ) (Fig. 2). The instantaneous risk of a severe exacerbation was 30% lower with budesonide/formoterol maintenance and reliever therapy versus budesonide/formoterol plus terbutaline (hazard ratio 0.70, 95% confidence interval , P = ) (Table 4). Time to first oral steroid use, first hospitalization and first emergency room treatment were all significantly prolonged in the budesonide/formoterol maintenance and reliever group versus budesonide/formoterol plus terbutaline (Table 4). FEV 1 Patients receiving budesonide/formoterol maintenance and reliever therapy had a significantly greater
4 Budesonide/formoterol in asthma 357 Table 1 Patient flow through the study Bud/form maintenance + reliever, n Bud/form maintenance + terbutaline, n Enrolled patients 3209 Randomized Discontinued Incorrect enrolment 3 3 Adverse event 8 12 Development of study-specific discontinuation criteria 6 13 Voluntary discontinuation Lost to follow-up Severe protocol non-compliance 7 7 Safety reasons 2 1 Other 8 14 Completed Table 2 Patients baseline characteristics and demographics Variable Bud/form maintenance + reliever (n = 1049) Bud/form maintenance + terbutaline (n = 1042) Male/female, n (%) 327/722 (31.2/68.8) 350/692 (33.6/66.4) Mean age, years (SD) 45.7 (14.5) 45.6 (14.5) Aged 65 years, n (%) 106 (10.1) 99 (9.5) Ethnicity, n (%) Asian 652 (62.2) 650 (62.4) White 332 (31.6) 332 (31.9) Other 65 (6.2) 60 (5.7) Median time since diagnosis, years (range) 12 (1 67) 12 (1 74) Smoking status, n (%) Never 890 (84.8) 890 (85.4) Current 40 (3.8) 42 (4.0) Former 119 (11.3) 110 (10.6) Median number of days since last exacerbation, n (range) 143 (3 366) 146 (9 366) Mean inhaled glucocorticosteroid dose at study entry, mg (SD) (208.5) (208.7) Mean BDP dose before study entry, mg (SD) (325.2) (324.2) LABA use prior to study entry, n (%) 636 (60.6) 650 (62.4) Mean FEV 1, L (SD) 1.93 (0.64) 1.93 (0.65) Mean FEV 1, % of predicted normal (14.65) (13.75) Mean FEV 1 reversibility, % (SD) (12.46) (10.80) Mean daily as-needed inhaler use, n (SD) 2.41 (1.55) 2.43 (1.58) Mean symptom score (SD) 1.96 (0.99) 1.99 (1.01) Mean symptom-free days, % (SD) (20.02) 9.83 (19.50) Mean as-needed inhaler-free days, % (SD) 9.33 (14.72) 9.39 (15.01) Mean asthma control days, % (SD) 6.22 (12.42) 6.37 (12.45) Mean night-time awakenings, % (SD) (35.68) (36.89) Average for the last 10 days prior to randomization. BDP, beclomethasone dipropionate; FEV 1, forced expiratory volume in 1 s; LABA, long-acting b 2-agonist; SD, standard deviation. increase in FEV 1 from baseline during treatment than patients receiving budesonide/formoterol plus terbutaline (adjusted mean change and L, respectively; mean difference L, 95% confidence interval ; P < 0.001). Diary card variables Throughout the study period, patients randomized to group had a lower daily mean use of as-needed medication compared with those randomized to budesonide/formoterol plus terbutaline (Fig. 3). Patients in the budesonide/formoterol maintenance and reliever group had more as-needed medicationfree days compared with those in the budesonide/ formoterol plus terbutaline group (Table 5). The group received additional budesonide during
5 358 T Atienza et al. Table 3 Incidence of severe exacerbations (by definition) in patients receiving budesonide/formoterol maintenance and reliever therapy, or budesonide/formoterol plus terbutaline Event Bud/form maintenance + reliever (n = 1049) Bud/form + terbutaline (n = 1042) Severe asthma exacerbations No. with at least 1 event 170 (16%) 229 (22%) Total no. of events Max no. of events/patient 10 6 No. of days with event Annual event rate Oral steroid use No. with at least 1 event 130 (12%) 168 (16%) Total no. of events Max no. of events/patient 4 5 No. of days with event ER treatment No. with at least 1 event 112 (11%) 151 (14%) Total no. of events Max no. of events/patient 9 6 No. of days with event Hospitalization No. with at least 1 event 11 (1%) 33 (3%) Total no. of events Max no. of events/patient 1 3 No. of days with event Hospitalization or ER treatment No. with at least 1 event 118 (11%) 162 (16%) Total no. of events Max no. of events/patient 10 6 No. of days with event ER, emergency room. as-needed use resulting in a mean daily exposure of 514 mg budesonide versus 320 mg budesonide in the maintenance-only group. Less oral steroids were used (on 1215 days) for exacerbations in the budesonide/formoterol maintenance and reliever group compared with 1697 days in the budesonide/formoterol plus terbutaline group. Data are not available on the dose or specific oral steroid used. Morning and evening peak expiratory flow also favoured the budesonide/formoterol maintenance and reliever group compared with the budesonide/ formoterol plus terbutaline group (P = 0.002; Table 5 and Fig. 4). Patient-perceived asthma symptoms favoured the budesonide/formoterol maintenance and reliever regimen with significant benefits versus budesonide/formoterol plus terbutaline for total asthma score (P = 0.025), daytime asthma symptom score (P = 0.025), proportion of symptom-free days (P = 0.016) and the proportion of asthma control days (P = 0.005) (Table 5). Fewer patients receiving budesonide/formoterol maintenance and reliever experienced mild exacerbations compared with those receiving budesonide/ formoterol plus terbutaline (71% vs 80%, respectively; hazard ratio 0.81, 95% confidence interval , P < ). The instantaneous risk of having a mild asthma exacerbation was decreased by 19% in the therapy group. ACQ During the study period, patients in the budesonide/ formoterol maintenance and reliever group had lower mean ACQ scores than patients in the budesonide/ formoterol plus terbutaline group, reflecting better asthma control (Supporting Information Table S1). The decrease (improvement) in ACQ score from baseline at the end of treatment was greater in the group versus the budesonide/formoterol plus terbutaline group (P < 0.001). In the budesonide/ formoterol maintenance and reliever group, 56% of patients had a clinically relevant decrease ( 0.5) in ACQ score versus 49% in the budesonide/formoterol plus terbutaline group. Safety outcomes Both treatments were well tolerated. A total of 602 budesonide/formoterol maintenance and reliever therapy patients (57.4%) and 599 (57.5%) budesonide/formoterol plus terbutaline patients experienced at least one adverse event (Supporting Table S2). The majority of adverse events were mild or moderate in intensity. The most frequently reported adverse events were nasopharyngitis, bronchitis and viral upper respiratory tract infection (Supporting Information Table S2). Asthma recorded as an adverse event occurred less frequently among budesonide/ formoterol maintenance and reliever therapy patients than budesonide/formoterol plus terbutaline
6 Budesonide/formoterol in asthma Patients with severe exacerbations (%) Weeks from randomization Numbers at risk Budesonide/formoterol maintenance and reliever therapy Budesonide/formoterol maintenance + terbutaline Figure 2 Time to first severe asthma exacerbation in patients receiving therapy (grey line) or budesonide/formoterol plus terbutaline (black line). Table 4 Hazard ratio (HR) for severe exacerbation in patients receiving budesonide/formoterol maintenance and reliever therapy, or budesonide/formoterol plus terbutaline Variable HR of time to event 95% CI P-value Severe asthma exacerbation Cox proportional hazard Poisson regression < Oral steroids Cox proportional hazard Poisson regression Hospitalization Cox proportional hazard Poisson regression NA NA NA ER treatment Cox proportional hazard Poisson regression < ER or hospitalization Cox proportional hazard Poisson regression < Budesonide/formoterol maintenance and reliever therapy vs. budesonide/formoterol plus terbutaline. CI, confidence interval; ER, emergency room; NA, not available.
7 360 Change from run-in patients (4.7% vs 7.2%). Adverse events were considered to be related to study treatment for 3.9% of therapy patients, and 3.5% of budesonide/formoterol plus terbutaline patients. One death was reported in each treatment group ( therapy: septic shock; budesonide/formoterol plus terbutaline: acute myocardial infarction); none of the deaths were related to asthma or considered by the investigator as related to study treatment. Serious adverse events other than death occurred in 4.0% and 7.1% of patients in the budesonide/formoterol maintenance and reliever therapy and budesonide/ formoterol plus terbutaline groups, respectively. Again, asthma recorded as a serious adverse event occurred less frequently in budesonide/formoterol maintenance and reliever therapy patients than those receiving budesonide/formoterol plus terbutaline (0.5% vs 3.0%). Eleven patients receiving budesonide/ formoterol maintenance and reliever therapy, and 12 receiving budesonide/formoterol plus terbutaline discontinued due to an adverse event. No clinically significant changes and no obvious differences between the two treatment groups were noted for any of the haematological, urinalysis and clinical chemistry variables monitored as part of the study. There were no clinically significant changes in mean values over time and no obvious differences between treatment groups for any vital signs or electrocardiogram. DISCUSSION Weeks since randomization Figure 3 Change from run-in in as-needed medication use in patients receiving budesonide/formoterol maintenance and reliever therapy (n = 1032; grey line) or budesonide/formoterol plus terbutaline (n = 1026; black line). T Atienza et al. The results offer further confirmation that therapy provides better asthma control, as evidenced by a prolongation of time to first severe exacerbation. Moreover, patients randomized to budesonide/ formoterol maintenance and reliever therapy experienced a 30% reduction in risk of severe asthma exacerbations. Benefits were also observed in the rate of each of the individual criteria used to define a severe asthma exacerbation, measures of lung function and most symptom-related variables. A similar benefit was observed when mild asthma exacerbations were considered, with a reduction in the total number of mild exacerbations experienced and a prolongation of the time to the first mild exacerbation. The findings of the current study support other studies that have evaluated budesonide/formoterol maintenance and reliever therapy compared with fixed-dose ICS/long-acting b 2-agonist plus reliever medications The results are also consistent with a recent meta-analysis of data from these studies, which confirmed that budesonide/formoterol maintenance and reliever therapy is significantly more effective at reducing severe asthma exacerbations than increasing the dose of ICS alone or with fixeddose ICS/long-acting b 2-agonist. 18 Further confidence in the results of the clinical database for budesonide/ formoterol maintenance and reliever therapy can be drawn from a recent assessment of 13 clinical trials in the context of the Grade of Recommendations, Assessment, Development and Evaluation system. 19 This assessment found no serious limits in the methodological study features and consistency between the studies in terms of extending the time to the first asthma exacerbation. The secondary variables provide a broader picture of the efficacy of budesonide/formoterol as maintenance and reliever therapy; patients randomized to budesonide/formoterol as maintenance and reliever therapy required less as-needed medication on a daily basis, recorded improved lung function (peak expiratory flow) in both the morning and evening, and reported fewer overall day-to-day asthma symptoms compared with those randomized to budesonide/ formoterol plus terbutaline. Improvements in ACQ scores also indicated that patients perceived an improvement in their asthma control that was significantly greater (P < 0.001) among those who received budesonide/formoterol as maintenance and reliever therapy than among those treated with budesonide/ formoterol plus terbutaline. Temporary dose increases of budesonide resulting from as-needed budesonide/formoterol use as a result of symptom worsening are likely to contribute to the overall efficacy of this treatment. It is thought that the improvements occur in the budesonide/ formoterol maintenance and reliever group because even though these patients require less as-needed medication than those in the budesonide/formoterol maintenance and formoterol as-needed group, when they do require reliever therapy, these patients receive both ICS and bronchodilator rather than just bronchodilator. As-needed treatment immediately following exposure to environmental triggers that lead to a temporary loss of symptom control is likely to result in an increase in controller therapy in line with disease activity. During periods when asthma control is stable, patients using the maintenance and reliever therapy approach default solely to maintenance budesonide/formoterol. Thus, budesonide/
8 Budesonide/formoterol in asthma 361 Table 5 Baseline, during treatment, mean change from baseline and mean difference in change from baseline in diary variables between patients receiving therapy and those receiving budesonide/formoterol plus terbutaline Variable Bud/form maintenance + reliever (n = 1034) Bud/form maintenance + terbutaline (n = 1026) Mean difference (Bud/Form maintenance + reliever Bud/Form maintenance + terbutaline) (95% CI) P-value Baseline Treatment Mean change Baseline Treatment Mean change Use of as-needed inhaler Total number of daily inhalations (-0.36 to -0.15) <0.001 Night-time use (-0.14 to -0.05) <0.001 Daytime use (-0.23 to -0.10) <0.001 As-needed-free days (%) (1.6 to 7.3) PEF (L/min) Morning (2.1 to 9.5) Evening (2.1 to 9.3) FEV1 (L) (0.015, 0.064) Asthma symptoms Total score (0 6) (-0.16 to -0.01) Night-time score (0 3) (-0.07 to 0.02) Daytime score (0 3) (-0.09 to -0.01) Awakenings (%) (-3.68 to 0.07) Symptom-free days (%) (0.7 to 6.5) Asthma control days (%) (1.3 to 7.1) Asthma control days: no asthma symptoms, no awakenings and no as-needed use. CI, confidence interval; FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.
9 362 T Atienza et al. a 350 number of and time to first severe asthma exacerbation, relieving the daily symptoms of asthma, and is well tolerated in patients with uncontrolled asthma. Morning PEF (L/min) Acknowledgements The study was funded by AstraZeneca. Editorial services were provided by Ian Wright, Wright Medical Communications Ltd, Hartford, UK, and funded by AstraZeneca. REFERENCES b Evening PEF (L/min) Weeks since randomization Weeks since randomization Figure 4 (a) Morning and (b) evening peak expiratory flow (PEF) in patients receiving budesonide/formoterol maintenance and reliever therapy (n = 1034; grey line) or budesonide/formoterol plus terbutaline (n = 1026; black line). formoterol maintenance and as-needed reliever therapy responds more effectively and efficiently to the natural variations in asthma control. Budesonide-containing reliever therapy can ensure that an increase in anti-inflammatory therapy is delivered as required during periods of deteriorating symptoms and increased need for reliever medication. All treatments were well tolerated, and no new or unexpected safety concerns were identified. The safety profile of budesonide/formoterol as maintenance and reliever therapy observed in the current study compares well with that observed in previous studies of this regimen and with other fixed-dose alternatives. 20 The most commonly reported adverse events in the current study were infections including nasopharyngitis, bronchitis and viral upper respiratory tract infections. This is consistent with the previous studies evaluating this regimen In conclusion, the current study provides further confirmation that budesonide/formoterol maintenance and reliever therapy is effective in reducing the 1 Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention [updated 2011]. Available from URL: 2 Greening AP, Ind PW, Northfield M et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344: O Byrne PM, Barnes PJ, Rodriguez-Roisin R et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: OPTIMA randomized trial. Am. J. Respir. Crit. Care Med. 2001; 164: Pauwels RA, Lofdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 1997; 337: Woolcock A, Lundback B, Ringdal N et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am. J. Respir. Crit. Care Med. 1996; 153: Humbert M, Andersson TLG, Buhl R. Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma. Eur. J. Allergy Clin. Immunol. 2008; 63: Partridge MR, van der Molen T, Myrseth SE et al. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulmon. Med. 2006; 6: Bousquet J, Boulet LP, Peters MJ et al. Budesonide/formoterol formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir. Med. 2007; 101: Kuna P, Peters MJ, Manjra AI et al. Effect of budesonide/ formoterol maintenance and reliever therapy on asthma exacerbations. Int. J. Clin. Pract. 2007; 61: O Byrne PM, Bisgaard H, Godard PP et al. Budesonide/ formoterol combination therapy as both maintenance and reliever medication in asthma. Am. J. Respir. Crit. Care Med. 2005; 171: Rabe KF, Atienza T, Magyar P et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006; 368: Rabe KF, Pizzichini E, Stallberg B et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-tomoderate asthma: a randomized, double-blind trial. Chest 2006; 129: Scicchitano R, Aalbers R, Ukena D et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr. Med. Res. Opin. 2004; 20: Lundborg M, Wille S, Bjermer L et al. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study. Curr. Med. Res. Opin. 2006; 22: Sears MR, Boulet LP, Laviolette M et al. Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma. Eur. Respir. J. 2008; 31:
10 Budesonide/formoterol in asthma Vogelmeier C, D Urzo A, Pauwels R et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur. Respir. J. 2005; 26: Demoly P, Louis R, Soes-Petersen U et al. Budesonide/ formoterol maintenance and reliever therapy versus conventional best practice. Respir. Med. 2009; 103: Edwards SJ, von Maltzahn R, Naya IP et al. Budesonide/ formoterol for maintenance and reliever therapy o asthma: a meta analysis of randomised controlled trials. Int. J. Clin. Pract. 2010; 64: Braido F, Baiardino I, Compalati E et al. Towards the Grade of Recommendations, Assessment, Development and Evaluation system: methods and results of budesonide/formoterol maintenance and reliever therapy research. Curr. Opin. Allergy Clin. Immunol. 2011; 11: Sears MR, Radner F. Safety of budesonide/formoterol maintenance and reliever therapy in asthma trial. Respir. Med. 2009; 103: Supporting information Additional Supporting Information may be found in the online version of this article: Table S1 Mean value change from baseline and treatment comparison for ACQ scores between patients receiving budesonide/ formoterol maintenance and reliever therapy and those receiving budesonide/formoterol plus terbutaline. Table S2 Incidence of the most common (>2%) adverse events.
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