Asthma
Conditions
Brief summary
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
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'
Interventions
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
DRUGbudesonode bid + terbutaline 'as needed'
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
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. 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 2. Male or Female, ≥12 years of age 3. Documented diagnosis of asthma for at least 6 months prior to Visit 1 4. Patients who are in need of GINA step 2 treatment 5. 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 6. 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 7. Patients should have reversible airway obstruction 8. 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
1. Patient has a history of life-threatening asthma including intubation and intensive care unit admission 2. 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 3. 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 4. Current or previous smoker with a smoking history of ≥ 10 pack years 5. Pregnancy, breast-feeding or planned pregnancy during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis | up to 52 weeks | Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation |
| Annual Severe Asthma Exacerbation Rate - Superiority Analysis | up to 52 weeks | Severe asthma exacerbations over the randomised treatment period, negative binomial model for superiority test evaluation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Study Specific Asthma Related Discontinuation | Day 1 up to 52 weeks | 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. |
| Average Change From Baseline in 'as Needed' Use | Week 0 up to 52 weeks | '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. |
| Change From Baseline in Percent of 'as Needed' Free Days | Week 0 up to 52 weeks | '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. |
| Number of Participants Experiencing at Least One Severe Asthma Exacerbation | Day 1 up to 52 weeks | 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. |
| Average Change From Baseline in Asthma Control Questionnaire (5-item Version) - ACQ-5 Score | Study weeks 0, 17, 34, 52 | 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. |
| Average Change From Baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) Score | Study weeks 0,17, 34, 52 | 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. |
| Percentage of Controller Use Days | Week 0 up to 52 weeks | 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. |
| Average Change From Baseline in Pre-bronchodilator FEV1 | Study weeks 0,17, 34, 52 | 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. |
Countries
Australia, Brazil, Bulgaria, Chile, Colombia, Czechia, France, Germany, Hungary, Mexico, New Zealand, Peru, Philippines, Poland, Romania, Russia, Saudi Arabia, Slovakia, South Africa, South Korea, Spain, Sweden, Thailand, Ukraine, Vietnam
Participant flow
Recruitment details
4215 patients were enrolled. 26 patients were randomised in error and hence never recieved treatment.
Pre-assignment details
Screening Details Eligibility was assessed at Visits 1, 2 and 3. IC was obtained at V1. At V2, patients stopped pre-study asthma medications and entered a 2 to 4 week run-in period on SABA as needed only (Bricanyl Turbuhaler 0.5 mg). Lung function was assessed by spirometry to confirm eligibility. Eligible patients were randomised at V3.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg) | 2,089 |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed' | 2,087 |
| Total | 4,176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Eligibility criteria not fulfilled | 4 | 8 |
| Overall Study | Lost to Follow-up | 27 | 35 |
| Overall Study | Other | 13 | 10 |
| Overall Study | Prematurely closed site | 4 | 2 |
| Overall Study | Severe non-compliance to protocol | 2 | 2 |
| Overall Study | Subject decision | 58 | 50 |
Baseline characteristics
| Characteristic | Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Total | Placebo Bid + Symbicort 'as Needed' (Experimental) |
|---|---|---|---|
| Age, Continuous | 40.7 Years STANDARD_DEVIATION 17.1 | 41.0 Years STANDARD_DEVIATION 17 | 41.3 Years STANDARD_DEVIATION 16.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 32 Participants | 68 Participants | 36 Participants |
| Race/Ethnicity, Customized Asian | 403 Participants | 802 Participants | 399 Participants |
| Race/Ethnicity, Customized Black or African American | 33 Participants | 67 Participants | 34 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 211 Participants | 422 Participants | 211 Participants |
| Race/Ethnicity, Customized White | 1406 Participants | 2814 Participants | 1408 Participants |
| Sex/Gender, Customized Female | 1289 Participants | 2597 Participants | 1308 Participants |
| Sex/Gender, Customized Male | 798 Participants | 1579 Participants | 781 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 2,089 | 1 / 2,087 |
| other Total, other adverse events | 491 / 2,089 | 519 / 2,087 |
| serious Total, serious adverse events | 66 / 2,089 | 73 / 2,087 |
Outcome results
Primary
Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis
Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis | 0.11 exacerbations per participant year |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis | 0.12 exacerbations per participant year |
Negative binomial model
Primary
Annual Severe Asthma Exacerbation Rate - Superiority Analysis
Severe asthma exacerbations over the randomised treatment period, negative binomial model for superiority test evaluation
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Annual Severe Asthma Exacerbation Rate - Superiority Analysis | 0.11 exacerbations per participant year |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Annual Severe Asthma Exacerbation Rate - Superiority Analysis | 0.12 exacerbations per participant year |
p-value: 0.75495% CI: [0.78, 1.2]Negative binomial model
Secondary
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.
Time frame: Week 0 up to 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Average Change From Baseline in 'as Needed' Use | -0.84 Number of inhalations per day |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Average Change From Baseline in 'as Needed' Use | -0.87 Number of inhalations per day |
95% CI: [0, 0.07]ANCOVA
Secondary
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.
Time frame: Study weeks 0, 17, 34, 52
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Average Change From Baseline in Asthma Control Questionnaire (5-item Version) - ACQ-5 Score | -0.35 Score |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Average Change From Baseline in Asthma Control Questionnaire (5-item Version) - ACQ-5 Score | -0.46 Score |
p-value: <0.00195% CI: [0.068, 0.15]Mixed Models Analysis
Secondary
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.
Time frame: Study weeks 0,17, 34, 52
Population: Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Average Change From Baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) Score | 0.335 AQLQ(S) overall score |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Average Change From Baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) Score | 0.431 AQLQ(S) overall score |
p-value: <0.00195% CI: [-0.137, -0.054]Mixed Models Analysis
Secondary
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.
Time frame: Study weeks 0,17, 34, 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Average Change From Baseline in Pre-bronchodilator FEV1 | 104.0 mL |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Average Change From Baseline in Pre-bronchodilator FEV1 | 136.6 mL |
p-value: 0.00395% CI: [-53.7, -11.4]Mixed Models Analysis
Secondary
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.
Time frame: Week 0 up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Change From Baseline in Percent of 'as Needed' Free Days | 41.01 Percentage of 'as needed' free days |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Change From Baseline in Percent of 'as Needed' Free Days | 47.86 Percentage of 'as needed' free days |
p-value: <0.00195% CI: [-8.37, -5.34]ANCOVA
Secondary
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.
Time frame: Day 1 up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Number of Participants Experiencing at Least One Severe Asthma Exacerbation | 177 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Number of Participants Experiencing at Least One Severe Asthma Exacerbation | 184 Participants |
p-value: 0.66495% CI: [0.777, 1.174]Regression, Cox
Secondary
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.
Time frame: Day 1 up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Number of Participants With Study Specific Asthma Related Discontinuation | 0 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Number of Participants With Study Specific Asthma Related Discontinuation | 4 Participants |
Secondary
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.
Time frame: Week 0 up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' (Experimental) | Percentage of Controller Use Days | 30.45 Percentage of days |
| Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) | Percentage of Controller Use Days | 67.92 Percentage of days |
p-value: <0.00195% CI: [-39.18, -35.77]ANOVA