A Clinical Study to Evaluate Symbicort Turbuhaler Used 'as Needed' in Adults and Adolescents With Asthma

Study Overview
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Brief Summary
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The purpose of this study is to test if Symbicort (budesonide/formoterol) Turbuhaler is effective in treating asthma when used 'as needed' in patients with milder asthma. The efficacy of Symbicort 'as needed' will be compared with Pulmicort (budesonide) Turbuhaler twice daily plus terbutaline Turbuhaler 'as needed'

Detailed Description
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A 52-week, double-blind, randomised, multi-centre, phase III, parallel-group study in patients 12 years and older with asthma, evaluating the efficacy and safety of Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' compared with Pulmicort (budesonide) Turbuhaler 200 μg twice daily plus terbutaline Turbuhaler 0.4 mg 'as needed'

Official Title
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A Clinical Study Comparing Symbicort 'as Needed' With Pulmicort Twice Daily Plus Terbutaline 'as Needed' in Adult and Adolescent Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: budesonide/formoterol 'as needed' + budesonide placebo bid
* Drug: budesonode bid + terbutaline 'as needed'


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. For patients under-age, signed informed consent from both the patient and the patient's parent/legal guardian is required Male or Female, ≥12 years of age Documented diagnosis of asthma for at least 6 months prior to Visit 1 Patients who are in need of GINA step 2 treatment Patients treated with a short acting inhaled bronchodilator(s) only should have pre-bronchodilator FEV1 ≥ 60 % of predicted normal (PN) and post-bronchodilator FEV1 ≥ 80 % PN Patients treated with low stable dose of ICS or leukotriene antagonists in addition to short acting inhaled bronchodilator(s) should have pre-bronchodilator FEV1 ≥80 % PN Patients should have reversible airway obstruction To be randomized patients must have used Bricanyl Turbuhaler as needed on at least 3 separate days during the last week of the run in period Exclusion Criteria: Patient has a history of life-threatening asthma including intubation and intensive care unit admission Patient has had an asthma worsening requiring change in treatment other than short acting inhaled bronchodilator(s) within 30 days prior to Visit 1 and from Visit 1 until randomization Patient has required treatment with oral, rectal or parenteral GCS within 30 days and/or depot parenteral GCS within 12 weeks prior to Visit 1 Current or previous smoker with a smoking history of ≥ 10 pack years Pregnancy, breast-feeding or planned pregnancy during the study

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Symbicort as needed+placebo Pulmicort bid<br>Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid | Drug: budesonide/formoterol 'as needed' + budesonide placebo bid<br>* Symbicort (budesonide/ formoterol) 160/4.5 μg powder for inhalation 'as needed' plus Pulmicort placebo 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment<br>|
| Active Comparator: Pulmicort bid + terbutaline as needed<br>Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed' | Drug: budesonode bid + terbutaline 'as needed'<br>* Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening) plus terbutaline 0.4 mg powder for inhalation 'as needed', 52-week treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis | Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation | up to 52 weeks | 
| Annual Severe Asthma Exacerbation Rate - Superiority Analysis | Severe asthma exacerbations over the randomised treatment period, negative binomial model for superiority test evaluation | up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing at Least One Severe Asthma Exacerbation | A severe exacerbation is defined as a deterioration of asthma requiring any of the following: use of systemic glucocorticosteroids (GCS) for at least 3 days, inpatient hospitalization, or emergency room visit due to asthma that required systemic steroids. | Day 1 up to 52 weeks | 
| Average Change From Baseline in Pre-bronchodilator FEV1 | The average change from baseline (baseline defined by measurement at week 0, prior to first dose of IP) to the treatment period average assessed over the entire treatment period in pre-bronchodilator FEV1 was derived by computing a contrast for the mean across the post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis. | Study weeks 0,17, 34, 52 | 
| Number of Participants With Study Specific Asthma Related Discontinuation | The following two criteria lead to discontinuation from the IP due to asthma related events: A severe asthma exacerbation with duration for more than 3 weeks, and/or three severe asthma exacerbations during 6 months. | Day 1 up to 52 weeks | 
| Average Change From Baseline in 'as Needed' Use | 'As-needed' use change from baseline over the randomised treatment period. Baseline was defined as the last 10 days of the run-in period. 'As needed' use was calculated as the cumulative doses of 'as-needed' medication over the randomised treatment period divided by the follow-up time (number of days - 1). ie, average number of inhalations per day. | Week 0 up to 52 weeks | 
| Change From Baseline in Percent of 'as Needed' Free Days | 'As needed' free days (%) change from baseline during randomised treatment period. An 'as-needed' free day was defined as a day and night with no use of 'as needed' medication. Variable analysed is the percentage (%) of 'as-needed' free days during the randomised treatment period. Baseline is defined by the last 10 days of the run-in period. | Week 0 up to 52 weeks | 
| Percentage of Controller Use Days | ICS controller use days (%) during the randomised treatment period is calculated as the cumulative days when any controller medication (containing ICS) was taken including maintenance (Pulmicort bid group) and 'as needed' medication (Symbicort 'as needed' group) and additional prescribed ICS for asthma (all treatment groups), divided by the number of days in the randomised treatment period. | Week 0 up to 52 weeks | 
| Average Change From Baseline in Asthma Control Questionnaire (5-item Version) - ACQ-5 Score | ACQ questionnaire contains five questions on patients' symptoms, which are assessed on a 7-point scale from 0 (representing good control) to 6 (representing poor control). The score is the mean score of all questions for which responses are provided. The average change from baseline to treatment period average in ACQ-5 was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis. | Study weeks 0, 17, 34, 52 | 
| Average Change From Baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) Score | AQLQ(S) consists of 32 questions in 4 domains. Each question is assessed on a 7-point scale from 1 to 7, with higher values indicating better health-related quality of life. The overall score is calculated as the mean score of all 32 items. The average change from baseline to treatment period average in AQLQ(S) overall score was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis. | Study weeks 0,17, 34, 52 |