The primary objective of this study was to compare the clinical efficacy of Symbicort^® 2x80/4.5 mcg OD plus Symbicort 80/4.5 mcg as-needed with that of Pulmicort^® 2x160 mcg OD plus Bricanyl Turbuhaler^® 0.4 mg as-needed.

The secondary objective of the study was safety, i.e. to investigate the safety of Symbicort Turbuhaler 80/4.5 mcg/inhalation, 2 inhalations once daily plus Symbicort Turbuhaler 80/4.5 mcg/inhalation as-needed, compared with Pulmicort Turbuhaler 160 mcg/inhalation, 2 inhalations once daily plus Bricanyl Turbuhaler 0.4 mg/dose as-needed. The safety evaluation took into account several safety variables with no particular variable chosen as the main one.

METHODS:

STUDY DESIGN

The study was double-blind, randomized, active-controlled, multi-centre and multi-national with a parallel group design comparing the efficacy and safety of Symbicort 80/4.5 mg/inhalation, 2 inhalations once daily plus Symbicort 80/4.5 µg/inhalation as-needed (Symbicort single-inhaler therapy, SiT) with that of Pulmicort 160 µg/inhalation, 2 inhalations once daily plus Bricanyl 0.4 mg/dose as-needed when given to adults and adolescents (12-80 years) for a period of 6 months in the treatment of asthma.

Target subject population and sample size

Male and female subjects, 12 to 80 years with asthma, previously treated with 200-500 mcg per day of inhaled glucocorticosteroids (IGCS). They had to have a forced expiratory volume in one second (FEV1 ) of 60-100% of predicted normal at Visit 1 and a reversibility in FEV1 from baseline of at least 12% at Visit 1 or 2, or a peak expiratory flow (PEF) variability of at least 12% on at least 3 out of the last 10 days of the run-in. During the last 10 days of the run-in period the subjects also had to have used at least 7 inhalations of the as-needed medication.

A total of 250 evaluable subjects with asthma derived from an estimated 300 recruited subjects were required per treatment group to detect a true difference in means of morning peak expiratory flow (mPEF) of 13 L/min with 90% power assuming that the common standard deviation was 45 L/min. This assumed a significance level of 5% and a two-sided alternative hypothesis.

Symbicort 80/4.5 mcg/dose, 2 inhalations once daily + Symbicort 80/4.5 mcg/dose as-needed or Pulmicort 160 mcg/dose, 2 inhalation once daily + Bricanyl Turbuhaler® 0.4 mg/dose as-needed. Doses were given in two inhalers identical between treatments, i.e. inhalers for maintenance (Symbicort or Pulmicort) were identical and inhalers for as-needed use (Symbicort or Bricanyl) were identical. Batch numbers were: Symbicort BF14, BF15, BH17, CC18; Pulmicort BH12; Bricanyl BL26, BG21-24, CC27.

The treatment arm with Symbicort, both as maintenance and as-needed, will be referred to as Symbicort SiT and the treatment arm with Pulmicort as maintenance and Bricanyl as-needed will be referred to as Pulmicort. 
 

DURATION OF TREATMENT

The study included a 2-week run-in period followed by a 6-month treatment period.

MAIN VARIABLES:

- EFFICACY

The primary efficacy variable was mPEF.

Secondary efficacy variables were FEV₁, evening PEF (ePEF), inhalations of as-needed medication, nights with awakening(s) due to asthma symptoms, asthma symptom scores, asthma-control days, mild asthma exacerbation days and severe asthma exacerbations. To increase the understanding of the different treatments, as-needed-free days and symptom-free days were added as variables to the statistical analyses. This was done before unblinding of study data.

- SAFETY

The following safety variables were to be assessed in all subjects: physical examination, pulse, blood pressure and adverse events (AEs). In a planned subgroup of 200 subjects (100 from each treatment group), the following additional safety variables were to be analysed: clinical chemistry, S-potassium, haematology, U-albumin, U-glucose, morning P-cortisol and ECG.

STATISTICAL METHODS

The full analysis set, as defined in ICH guideline E9, was used in all efficacy and safety analyses.

The change in average mPEF from the run-in to the treatment period was analysed using an analysis of variance model with treatment and country as fixed factors and the run-in period average as a covariate. The treatment difference was estimated from the model and 95% confidence limits were calculated. Change in average value from the run-in to the treatment period for ePEF, inhalations of as-needed medication, nights with awakening(s) due to asthma symptoms, asthma symptom scores, asthma-control days, symptom-free days and as-needed-free days were analysed in the same way as for mPEF.

The safety variables were analysed by means of descriptive statistics and qualitative analysis.

SUBJECT POPULATION

Table S1: Treatment group comparison of demographic and disease data. For categorical data, frequencies are given, for other data mean values and ranges.

The subjects recruited in the study were patients with mild to moderate asthma, i.e., the population intended according to the study protocol. The treatment groups were generally well balanced in demographic and baseline characteristics. Discontinuations of study treatment were relatively rare in all treatment groups.

RESULTS

- EFFICACY RESULTS

Symbicort SiT (Symbicort 80/4.5 mcg, 2 inhalations once daily plus as-needed) was shown to be more efficacious than conventional treatment with Pulmicort 160 mcg, 2 inhalations once daily plus Bricanyl as-needed, as demonstrated by an effect on the primary variable, mPEF, and all secondary variables, with the exception of nights with awakenings due to asthma symptoms (not statistically significant, but numerical difference in favour of Symbicort SiT).

Asthma control was improved with Symbicort SiT, as shown by reduction in severe and mild exacerbations and improvements in all symptom-related variables. During a severe exacerbation both asthma symptoms and use of as-needed medication were reduced in the Symbicort SiT group compared to Pulmicort.

Overall steroid load was reduced with Symbicort SiT, as shown by a reduction in both inhaled and oral GCS use. A summary of the results are shown in table S2

Table S2. Summary of result for efficacy variables. 

 ePEF evening peak expiratory flow; FEV1 forced expiratory volume in one second; mPEF morning peak expiratory flow; NA not applicable; SiT single-inhaler therapy.

 

- SAFETY RESULTS

Table S3. Number (%) of subjects who had an adverse event in any category (safety population)

 

 

Table S4. Adverse events by preferred term: Number (%) of subjects with the most commonly reported adverse events, sorted by decreasing order of frequency as summarised over all treatment groups (safety population) 

 

Overall, the reported AEs, including serious adverse events and discontinuations from treatment with investigational product due to AEs do not give rise to any new safety concerns. No clinically important differences were identified in this study between treatment groups or in individual subjects from baseline to end-of-treatment in clinical laboratory variables, ECG or vital signs.

Reference:

Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T, Lier PA, Jorup C. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006;129:246-56