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: 1) terbutaline Turbuhaler® 'as needed' and with 2) Pulmicort (budesonide) Turbuhaler® twice daily plus terbutaline Turbuhaler® 'as needed'.
Detailed description
A 52-week, double-blind, randomised, multi-centre, parallel-group, Phase III 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 terbutaline Turbuhaler® 0.4 mg 'as needed' and 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
DRUGterbutaline 'as needed' + placebo budesonide bid
Terbutaline 0.4 mg powder for inhalation 'as needed' plus placebo Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment
DRUGbudesonide 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 Step 2 treatment according to Global Initiative for Asthma guidelines 5. Patients treated with 'as needed' inhaled short-acting bronchodilator(s) only should have pre-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥ 60 % of Predicted Normal (PN) and post-bronchodilator FEV1 ≥ 80 % PN 6. Patients treated with low stable dose of inhaled corticosteroid or leukotriene antagonist in addition to 'as needed' use of inhaled short-acting 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 inhaled short-acting bronchodilator(s) within 30 days prior to Visit 1 or between Visits 1 and 2; or a treatment other than Bricanyl Turbuhaler from Visit 2 until randomization 3. Patient has required treatment with oral, rectal or parenteral glucocorticosteroids (GCS) within 30 days and/or depot parenteral GCS within 12 weeks prior to Visit 1 4. Smoker (current or previous) 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 |
|---|---|---|
| 'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) | Weekly, up to 52 weeks | A well-controlled asthma week is defined as the fulfilment of both conditions A) and B) below: A) Two or more of the following criteria are fulfilled: - No more than 2 days with a daily asthma symptom score \>1 - No more than 2 days of 'as needed' medication use, up to a maximum of 4 occasions per week (multiple occasions per day should be regarded as separate occasions) - Morning PEF ≥80% of Predicted Normal every day B) Both of the following criteria are fulfilled: - No nighttime awakenings due to asthma - No additional inhaled and/or systemic glucocorticosteroid treatment due to asthma. The binary variable well-controlled asthma week was derived for each patient and study week. In addition, for each week, the percent of patients with well-controlled asthma week was derived. It is required that the eDiary had to be completed on at least 5 days in a week to be a well-controlled asthma week. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation | Day 1 up to 52 weeks | A moderate exacerbation is defined as a deterioration of asthma requiring a change in treatment, i.e. initiation of prescribed additional ICS treatment to avoid progression of the worsening of asthma to a severe 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 |
| Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) | Study weeks 0,4,16,28,40,52 | Overall estimate of FEV1 (mL) pre-bronchodilator change from baseline. Baseline is the measurement at Visit 3 (prior to first dose of Investigational Product) from MMRM (mixed model repeated measures analysis). |
| Average Change From Baseline in Morning Peak Expiratory Flow (PEF) | up to 52 weeks | Morning peak expiratory flow (eDiary) change from baseline over the randomised treatment period. Baseline is defined as the mean of all non-missing morning measurements during the last 10 days of the run-in period. |
| Average Change From Baseline in Evening PEF | up to 52 weeks | Evening peak expiratory flow (eDiary) change from baseline during the randomised treatment period. Baseline is defined as the mean of all non-missing evening measurements during the last 10 days of the run-in period. |
| Average Change From Baseline in Number of Inhalations of 'as Needed' Medication. | up to 52 weeks | 'As needed' inhalations change from baseline over the randomised treatment period. Baseline is 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. |
| Average Change From Baseline in Asthma Symptom Score | up to 52 weeks | Asthma symptom score (eDiary) change from baseline during the randomised treatment period. Symptom score is entered morning and evening by the patient on a 4-point scale from 0 to 3 with higher values indicating more severe symptoms. Asthma symptom score is then the sum of the day and night scores, which implies a range of scores from 0 - 6, with higher values indicating more severe symptoms. Baseline is defined as the mean of all non-missing measurements during the last 10 days of the run-in period. |
| Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma | up to 52 weeks | Night-time awakenings (%) due to asthma change from baseline. Variable analysed is the proportion (%) of nights during the relevant period with night-time awakenings. Baseline refers to the last 10 nights of the run-in period. |
| Change From Baseline in Percentage of Symptom-free Days | up to 52 weeks | Symptom-free days (%) change from baseline during the randomised treatment period.Variable analysed is the proportion (%) of symptom-free days during the relevant period. Baseline refers to the last 10 days of the run-in period. |
| Annual Moderate or Severe Asthma Exacerbation Rate | up to 52 weeks | Moderate or severe asthma exacerbations during the randomised treatment period. |
| Change From Baseline in Percentage of Asthma Control Days | up to 52 weeks | Asthma control days (%) change from baseline. An asthma control day is defined as the fulfilment of all of the following criteria; a day and night with no asthma symptoms, a night with no awakenings due to asthma symptoms and a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of asthma control days during the randomised treatment period. Baseline refers to the last 10 days of the run-in period. |
| Number of Patients With Study Specific Asthma Related Discontinuation | up to 52 weeks | Study specific asthma related discontinuation |
| Poorly Controlled Asthma Weeks | Weekly for up to 52 weeks | A poorly-controlled asthma week is defined as a week meeting any one of the following conditions: Two or more consecutive days with awakenings due to asthma on both nights; A recorded use of 'as needed' medication for symptom relief of at least 3 occasions per day, for at least 2 consecutive days; Additional systemic GCS treatment required for severe exacerbation. If there were sufficient data within a week available to confirm the week was not poorly-controlled, the week is labelled as 'does not meet criteria for poorly-controlled'. |
| Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma | Day 1 up to 52 weeks | Additional steroids for asthma includes any additional inhaled and/or systemic glucocorticosteroids treatment due to asthma while in the randomised treatment period. |
| Average Change From Baseline in Asthma Control Questionnaire (ACQ-5) | Study weeks 0,4,16,28,40,52 | Asthma Control Questionnaire 5-item version score change from baseline. 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. |
| Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S)) | Study weeks 0,16,28,40,52 | Asthma Quality of Life Questionnaire Standardised Version (AQLQ (S) overall score change from baseline. 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. |
| Percentage of Controller Use Days | up to 52 weeks | ICS controller use days (%) during the randomised treatment period is calculated as the cumulative number of 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 exacerbations and/or long term poor asthma control (all treatment groups), divided by the number of days in the randomised treatment period. |
| Annual Severe Asthma Exacerbation Rate | up to 52 weeks | Severe asthma exacerbations over the randomised treatment period. |
| Change From Baseline in Percentage of 'As Needed' Free Days | up to 52 weeks | 'As needed' free days (%) change from baseline during the randomised treatment period. An 'as needed' free day is defined as a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of 'as needed' free days during the relevant period. Baseline refers to the last 10 days of the run-in period. |
Countries
Australia, Brazil, Bulgaria, Canada, Chile, China, Hungary, Mexico, Peru, Philippines, Poland, Romania, Russia, South Africa, South Korea, Ukraine, United Kingdom, Vietnam
Participant flow
Recruitment details
5721 patients enrolled; 5003 run-in, 718 not run-in; 3849 randomised, 1154 not randomised: 1022 did not meet incl/excl criteria, 4 adverse event, 5 severe non-compliance to protocol, 104 subject decision, 7 subject lost to follow-up, 12 other reason.
Pre-assignment details
Eligibility was assessed at Visits 1, 2, 3. IC obtained at V1. At V2, eligible patients stopped prescribed asthma medication and entered a 2-4 week run-in period, treated only with SABA Bricanyl Turbuhaler 0.5 mg, 'as needed'. Lung function was performed by spirometry to confirm eligibility. Eligible patients were randomised at Visit 3.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Bid + Symbicort 'as Needed' Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg) | 1,277 |
| Placebo Bid + Terbutaline 'as Needed' Placebo for budesonide (Placebo Turbuhaler) + Terbutaline Turbuhaler 0.4 mg 'as needed' | 1,277 |
| Pulmicort Bid + Terbutaline 'as Needed' Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4 mg 'as needed' | 1,282 |
| Total | 3,836 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 15 | 9 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Eligibility criteria not fulfilled | 9 | 14 | 8 |
| Overall Study | Lost to Follow-up | 3 | 12 | 11 |
| Overall Study | Other | 20 | 25 | 20 |
| Overall Study | Protocol Violation | 16 | 13 | 15 |
| Overall Study | Study specific withdrawal criteria | 4 | 21 | 6 |
| Overall Study | Withdrawal by Subject | 75 | 93 | 77 |
Baseline characteristics
| Characteristic | Placebo Bid + Symbicort 'as Needed' | Placebo Bid + Terbutaline 'as Needed' | Pulmicort Bid + Terbutaline 'as Needed' | Total |
|---|---|---|---|---|
| Age, Customized >=12 - <18 | 161 Participants | 144 Participants | 173 Participants | 478 Participants |
| Age, Customized >=18 - <50 | 711 Participants | 739 Participants | 736 Participants | 2186 Participants |
| Age, Customized >=50 - <65 | 308 Participants | 315 Participants | 285 Participants | 908 Participants |
| Age, Customized >=65 - <85 | 97 Participants | 78 Participants | 87 Participants | 262 Participants |
| Age, Customized >=85 | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 74 Participants | 73 Participants | 73 Participants | 220 Participants |
| Race/Ethnicity, Customized Asian | 340 Participants | 336 Participants | 347 Participants | 1023 Participants |
| Race/Ethnicity, Customized Black Or African American | 24 Participants | 33 Participants | 24 Participants | 81 Participants |
| Race/Ethnicity, Customized Native Hawaiian Or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 117 Participants | 109 Participants | 110 Participants | 336 Participants |
| Race/Ethnicity, Customized White | 721 Participants | 726 Participants | 728 Participants | 2175 Participants |
| Sex: Female, Male Female | 777 Participants | 771 Participants | 797 Participants | 2345 Participants |
| Sex: Female, Male Male | 500 Participants | 506 Participants | 485 Participants | 1491 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,277 | 0 / 1,277 | 2 / 1,282 |
| other Total, other adverse events | 295 / 1,277 | 378 / 1,277 | 360 / 1,282 |
| serious Total, serious adverse events | 38 / 1,277 | 50 / 1,277 | 37 / 1,282 |
Outcome results
Primary
'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No)
A well-controlled asthma week is defined as the fulfilment of both conditions A) and B) below: A) Two or more of the following criteria are fulfilled: - No more than 2 days with a daily asthma symptom score \>1 - No more than 2 days of 'as needed' medication use, up to a maximum of 4 occasions per week (multiple occasions per day should be regarded as separate occasions) - Morning PEF ≥80% of Predicted Normal every day B) Both of the following criteria are fulfilled: - No nighttime awakenings due to asthma - No additional inhaled and/or systemic glucocorticosteroid treatment due to asthma. The binary variable well-controlled asthma week was derived for each patient and study week. In addition, for each week, the percent of patients with well-controlled asthma week was derived. It is required that the eDiary had to be completed on at least 5 days in a week to be a well-controlled asthma week.
Time frame: Weekly, up to 52 weeks
Population: Full analysis set. Patients with no evaluable weeks are not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | 'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) | 34.4 Percentage | Standard Deviation 36.02 |
| Placebo Bid + Terbutaline 'as Needed' | 'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) | 31.1 Percentage | Standard Deviation 34.9 |
| Pulmicort Bid + Terbutaline 'as Needed' | 'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) | 44.4 Percentage | Standard Deviation 39.1 |
p-value: 0.04695% CI: [1, 1.3]Regression, Logistic
95% CI: [0.57, 0.73]Regression, Logistic
Secondary
Annual Moderate or Severe Asthma Exacerbation Rate
Moderate or severe asthma exacerbations during the randomised treatment period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Annual Moderate or Severe Asthma Exacerbation Rate | 0.14 exacerbations per year |
| Placebo Bid + Terbutaline 'as Needed' | Annual Moderate or Severe Asthma Exacerbation Rate | 0.36 exacerbations per year |
| Pulmicort Bid + Terbutaline 'as Needed' | Annual Moderate or Severe Asthma Exacerbation Rate | 0.15 exacerbations per year |
p-value: <0.00195% CI: [0.32, 0.49]Negative binomial model
p-value: 0.66395% CI: [0.74, 1.21]Negative binomial model
Secondary
Annual Severe Asthma Exacerbation Rate
Severe asthma exacerbations over the randomised treatment period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Annual Severe Asthma Exacerbation Rate | 0.07 exacerbations per year |
| Placebo Bid + Terbutaline 'as Needed' | Annual Severe Asthma Exacerbation Rate | 0.20 exacerbations per year |
| Pulmicort Bid + Terbutaline 'as Needed' | Annual Severe Asthma Exacerbation Rate | 0.09 exacerbations per year |
p-value: <0.00195% CI: [0.27, 0.49]Negative binomial model
p-value: 0.27995% CI: [0.59, 1.16]Negative binomial model
Secondary
Average Change From Baseline in Asthma Control Questionnaire (ACQ-5)
Asthma Control Questionnaire 5-item version score change from baseline. 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.
Time frame: Study weeks 0,4,16,28,40,52
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Asthma Control Questionnaire (ACQ-5) | -0.33 units on a scale |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Control Questionnaire (ACQ-5) | -0.17 units on a scale |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Control Questionnaire (ACQ-5) | -0.48 units on a scale |
p-value: <0.00195% CI: [-0.203, -0.105]Mixed Models Analysis
p-value: <0.00195% CI: [0.101, 0.198]Mixed Models Analysis
Secondary
Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S))
Asthma Quality of Life Questionnaire Standardised Version (AQLQ (S) overall score change from baseline. 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.
Time frame: Study weeks 0,16,28,40,52
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S)) | 0.313 units on a scale |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S)) | 0.186 units on a scale |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S)) | 0.415 units on a scale |
p-value: <0.00195% CI: [0.074, 0.181]Mixed Models Analysis
p-value: <0.00195% CI: [-0.155, -0.049]Mixed Models Analysis
Secondary
Average Change From Baseline in Asthma Symptom Score
Asthma symptom score (eDiary) change from baseline during the randomised treatment period. Symptom score is entered morning and evening by the patient on a 4-point scale from 0 to 3 with higher values indicating more severe symptoms. Asthma symptom score is then the sum of the day and night scores, which implies a range of scores from 0 - 6, with higher values indicating more severe symptoms. Baseline is defined as the mean of all non-missing measurements during the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Asthma Symptom Score | -0.23 units on a scale |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Symptom Score | -0.11 units on a scale |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Asthma Symptom Score | -0.32 units on a scale |
p-value: <0.00195% CI: [-0.18, -0.06]ANCOVA
p-value: 0.00495% CI: [0.03, 0.15]ANCOVA
Secondary
Average Change From Baseline in Evening PEF
Evening peak expiratory flow (eDiary) change from baseline during the randomised treatment period. Baseline is defined as the mean of all non-missing evening measurements during the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Evening PEF | -11.20 L/min |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Evening PEF | -22.15 L/min |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Evening PEF | -4.97 L/min |
p-value: <0.00195% CI: [6.99, 14.9]ANCOVA
p-value: 0.00295% CI: [-10.18, -2.29]ANCOVA
Secondary
Average Change From Baseline in Morning Peak Expiratory Flow (PEF)
Morning peak expiratory flow (eDiary) change from baseline over the randomised treatment period. Baseline is defined as the mean of all non-missing morning measurements during the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Morning Peak Expiratory Flow (PEF) | -3.97 L/min |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Morning Peak Expiratory Flow (PEF) | -15.92 L/min |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Morning Peak Expiratory Flow (PEF) | 6.01 L/min |
p-value: <0.00195% CI: [7.89, 16]ANCOVA
p-value: <0.00195% CI: [-14.03, -5.93]ANCOVA
Secondary
Average Change From Baseline in Number of Inhalations of 'as Needed' Medication.
'As needed' inhalations change from baseline over the randomised treatment period. Baseline is 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: up to 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Number of Inhalations of 'as Needed' Medication. | -0.95 Number of inhalations per day | Standard Deviation 0.82 |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Number of Inhalations of 'as Needed' Medication. | -0.82 Number of inhalations per day | Standard Deviation 0.92 |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Number of Inhalations of 'as Needed' Medication. | -1.06 Number of inhalations per day | Standard Deviation 0.9 |
Secondary
Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1)
Overall estimate of FEV1 (mL) pre-bronchodilator change from baseline. Baseline is the measurement at Visit 3 (prior to first dose of Investigational Product) from MMRM (mixed model repeated measures analysis).
Time frame: Study weeks 0,4,16,28,40,52
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) | 65 mL |
| Placebo Bid + Terbutaline 'as Needed' | Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) | 11.2 mL |
| Pulmicort Bid + Terbutaline 'as Needed' | Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) | 119.3 mL |
p-value: <0.00195% CI: [29.1, 78.5]Mixed Models Analysis
p-value: <0.00195% CI: [-78.8, -29.8]Mixed Models Analysis
Secondary
Change From Baseline in Percentage of 'As Needed' Free Days
'As needed' free days (%) change from baseline during the randomised treatment period. An 'as needed' free day is defined as a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of 'as needed' free days during the relevant period. Baseline refers to the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Change From Baseline in Percentage of 'As Needed' Free Days | 44.2 % of days | Standard Deviation 31 |
| Placebo Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of 'As Needed' Free Days | 45.0 % of days | Standard Deviation 30.7 |
| Pulmicort Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of 'As Needed' Free Days | 51.7 % of days | Standard Deviation 30.6 |
Secondary
Change From Baseline in Percentage of Asthma Control Days
Asthma control days (%) change from baseline. An asthma control day is defined as the fulfilment of all of the following criteria; a day and night with no asthma symptoms, a night with no awakenings due to asthma symptoms and a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of asthma control days during the randomised treatment period. Baseline refers to the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Change From Baseline in Percentage of Asthma Control Days | 13.2 % of days | Standard Deviation 23.9 |
| Placebo Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of Asthma Control Days | 12.8 % of days | Standard Deviation 23.3 |
| Pulmicort Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of Asthma Control Days | 18.5 % of days | Standard Deviation 28.4 |
Secondary
Change From Baseline in Percentage of Symptom-free Days
Symptom-free days (%) change from baseline during the randomised treatment period.Variable analysed is the proportion (%) of symptom-free days during the relevant period. Baseline refers to the last 10 days of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Change From Baseline in Percentage of Symptom-free Days | 4.2 % of days | Standard Deviation 25.9 |
| Placebo Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of Symptom-free Days | 1.3 % of days | Standard Deviation 24.8 |
| Pulmicort Bid + Terbutaline 'as Needed' | Change From Baseline in Percentage of Symptom-free Days | 6.8 % of days | Standard Deviation 27.6 |
Secondary
Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma
Night-time awakenings (%) due to asthma change from baseline. Variable analysed is the proportion (%) of nights during the relevant period with night-time awakenings. Baseline refers to the last 10 nights of the run-in period.
Time frame: up to 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma | -7.5 % of nights | Standard Deviation 24 |
| Placebo Bid + Terbutaline 'as Needed' | Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma | -4.6 % of nights | Standard Deviation 23.4 |
| Pulmicort Bid + Terbutaline 'as Needed' | Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma | -9.8 % of nights | Standard Deviation 22.7 |
Secondary
Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation
A moderate exacerbation is defined as a deterioration of asthma requiring a change in treatment, i.e. initiation of prescribed additional ICS treatment to avoid progression of the worsening of asthma to a severe 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' | Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation | 131 Participants |
| Placebo Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation | 274 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation | 143 Participants |
p-value: <0.00195% CI: [0.348, 0.528]Regression, Cox
p-value: 0.43695% CI: [0.718, 1.153]Regression, Cox
Secondary
Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma
Additional steroids for asthma includes any additional inhaled and/or systemic glucocorticosteroids treatment due to asthma while in the randomised treatment period.
Time frame: Day 1 up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma | 164 Participants |
| Placebo Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma | 345 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma | 187 Participants |
p-value: <0.00195% CI: [0.343, 0.497]Regression, Cox
p-value: 0.17595% CI: [0.701, 1.067]Regression, Cox
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' | Number of Participants Experiencing at Least One Severe Asthma Exacerbation | 71 Participants |
| Placebo Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Severe Asthma Exacerbation | 152 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' | Number of Participants Experiencing at Least One Severe Asthma Exacerbation | 78 Participants |
p-value: <0.00195% CI: [0.328, 0.577]Regression, Cox
p-value: 0.52495% CI: [0.653, 1.242]Regression, Cox
Secondary
Number of Patients With Study Specific Asthma Related Discontinuation
Study specific asthma related discontinuation
Time frame: up to 52 weeks
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Number of Patients With Study Specific Asthma Related Discontinuation | 4 Participants |
| Placebo Bid + Terbutaline 'as Needed' | Number of Patients With Study Specific Asthma Related Discontinuation | 21 Participants |
| Pulmicort Bid + Terbutaline 'as Needed' | Number of Patients With Study Specific Asthma Related Discontinuation | 6 Participants |
Secondary
Percentage of Controller Use Days
ICS controller use days (%) during the randomised treatment period is calculated as the cumulative number of 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 exacerbations and/or long term poor asthma control (all treatment groups), divided by the number of days in the randomised treatment period.
Time frame: up to 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Percentage of Controller Use Days | 30.8 % of days | Standard Deviation 28.7 |
| Placebo Bid + Terbutaline 'as Needed' | Percentage of Controller Use Days | 5.6 % of days | Standard Deviation 16.8 |
| Pulmicort Bid + Terbutaline 'as Needed' | Percentage of Controller Use Days | 85.6 % of days | Standard Deviation 19.5 |
Secondary
Poorly Controlled Asthma Weeks
A poorly-controlled asthma week is defined as a week meeting any one of the following conditions: Two or more consecutive days with awakenings due to asthma on both nights; A recorded use of 'as needed' medication for symptom relief of at least 3 occasions per day, for at least 2 consecutive days; Additional systemic GCS treatment required for severe exacerbation. If there were sufficient data within a week available to confirm the week was not poorly-controlled, the week is labelled as 'does not meet criteria for poorly-controlled'.
Time frame: Weekly for up to 52 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Bid + Symbicort 'as Needed' | Poorly Controlled Asthma Weeks | 7.7 weeks | Standard Deviation 13.3 |
| Placebo Bid + Terbutaline 'as Needed' | Poorly Controlled Asthma Weeks | 9.7 weeks | Standard Deviation 13.8 |
| Pulmicort Bid + Terbutaline 'as Needed' | Poorly Controlled Asthma Weeks | 6.7 weeks | Standard Deviation 12.7 |