Asthma
Conditions
Keywords
Symbicort pMDI, Asthma, safety, budesonide
Brief summary
The purpose of the study is to evaluate the safety of Symbicort compared to inhaled corticosteroid alone during 6 months in adult and adolescent patients with asthma
Detailed description
A 26 week, randomized, double-blind, parallel-group, active controlled, multicenter, multinational safety study evaluating the risk of serious asthma-related events during treatment with Symbicort®, a fixed combination of inhaled corticosteroid (ICS) (budesonide) and a long acting β2-agonist (LABA) (formoterol) as compared to treatment with ICS (budesonide) alone in adult and adolescent (≥12 years of age) patients with asthma.
Interventions
DRUGSymbicort pMDI
Patients were randomized to Symbicort and assigned to one of the following treatments (based upon ACQ at baseline and prior asthma therapy): Symbicort pMDI 80/4.5 μg x 2 actuations bid (morning and evening) or Symbicort pMDI 160/4.5 μg x 2 actuations bid (morning and evening), for oral inhalation.
DRUGbudesonide pMDI
Patients were randomized to budesonide and assigned to one of the following treatments (based upon ACQ at baseline and prior asthma therapy): budesonide pMDI 80 μg x 2 actuations bid (morning and evening) or budesonide pMDI 160 μg x 2 actuations bid (morning and evening), for oral inhalation.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed informed consent/ paediatric assent (if applicable) prior to any study specific procedures including medication withdrawal * Male or Female, ≥12 years of age * Documented clinical diagnosis of asthma for at least 1 year prior to Visit 2 * Patient must have history of at least 1 asthma exacerbation including one of the following: * requiring treatment with systemic corticosteroids * an asthma-related hospitalization between 4 weeks and 12 months prior to randomization * Current Asthma Therapy: Patients must be appropriately using one of the treatments for asthma listed in the protocol combined with achieving certain results when recording an Asthma Control Questionnaire
Exclusion criteria
* Patient has a history of life-threatening asthma. Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea requiring non-invasive ventilatory support. * Patient has required treatment with systemic corticosteroids (tablets, suspensions or injectable) for any reason within 4 weeks prior to Visit 2 * Patient has an ongoing exacerbation, defined as a worsening of asthma that requires treatment with systemic corticosteroids (tablets, suspension, or injectable) * An asthma exacerbation within 4 weeks of randomization or more than 4 separate exacerbations in the 12 months preceding randomization or more than 2 hospitalizations for treatment of asthma in the 12 months preceding randomization * Patient has a respiratory infection or other viral/bacterial illness, or is recovering from such an illness at the time of Visit 2 that, in the investigator's opinion, will interfere with the patient's lung function * Patient must not meet unstable asthma severity criteria as listed in the protocol * Peak expiratory flow must not be below 50% o predicted normal * Pregnancy, breast-feeding or planned pregnancy during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing an Event in the Composite Endpoint (Asthma-related Death, Asthma-related Intubation or Asthma-related Hospitalization) | Up to 27 weeks | Number of participants experiencing an event in the composite endpoint (asthma-related death, asthma-related intubation or asthma-related hospitalization), using events adjudicated and confirmed by the Joint Adjudication Committee. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated. |
| Number of Participants Experiencing an Event Included in the Definition of Asthma Exacerbation | Up to 26 weeks | Number of participants experiencing an event included in the definition of asthma exacerbation. An asthma exacerbation was defined as a deterioration of asthma requiring systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency room visit due to asthma that required systemic corticosteroids. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Puffs of Rescue Medication Per 24 Hours | Daily up to 26 weeks | Mean number of puffs of rescue medication per day (24 hours) during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide. |
| Asthma Control Questionnaire (ACQ6) | baseline, day 28, day 84, day 182 | The outcome variable for ACQ6 was the difference between the average of values recorded during the treatment period (day 28, day 84 and day 182) and the baseline measure. Analysis of covariance (ANCOVA) model, including the fixed factors of treatment and strata by incoming control/asthma treatment and baseline ACQ6 as covariate was used to compare Symbicort and budesonide. The asthma control questionnaire, ACQ6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. |
| Percent of Days With no Asthma Symptoms | Daily up to 26 weeks | Percent of days with no asthma symptoms during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide. |
| Number of Participants Experiencing Discontinuation of Investigational Product Due to a Protocol Defined Asthma Exacerbation | Up to 26 weeks | Number of participants experiencing discontinuation of investigational product due to a protocol defined asthma exacerbation. An asthma exacerbation was defined as a deterioration of asthma requiring systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency room visit due to asthma that required systemic corticosteroids. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated. |
| Percent of Nights With Awakening(s) Due to Asthma | Daily up to 26 weeks | Percent of nights with awakening(s) due to asthma during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide. |
| Percent of Days With Activity Limitation Due to Asthma | Daily up to 26 weeks | Percent of days with activity limitation due to asthma during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide. |
Countries
Argentina, Brazil, Bulgaria, Chile, Colombia, Czechia, France, Germany, India, Italy, Mexico, Panama, Peru, Philippines, Poland, Puerto Rico, Romania, Russia, Slovakia, South Africa, South Korea, Thailand, Ukraine, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
This study started with an assessment visit where inclusion/exclusion criteria were reviewed and informed consent obtained. Eligible patients were randomized at the next visit. Patients then entered a 26 weeks double-blind treatment period followed by a 1 week follow-up telephone contact. Patients were recruited in 25 countries with 25% in the US.
Pre-assignment details
Eligible adult and adolescent patients were stratified based upon assessment of ACQ and prior asthma therapy and randomized 1:1 to double-blind Symbicort or budesonide. 12460 patients were enrolled (informed consent received) and 11693 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Symbicort Patients were randomized to Symbicort and assigned to one of the following treatments (based upon ACQ at baseline and prior asthma therapy): Symbicort pMDI 80/4.5 μg x 2 actuations bid (morning and evening) or Symbicort pMDI 160/4.5 μg x 2 actuations bid (morning and evening). | 5,846 |
| Budesonide Patients were randomized to budesonide and assigned to one of the following treatments (based upon ACQ at baseline and prior asthma therapy): budesonide pMDI 80 μg x 2 actuations bid (morning and evening) or budesonide pMDI 160 μg x 2 actuations bid (morning and evening). | 5,847 |
| Total | 11,693 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | CRF termination module not completed. | 0 | 1 |
| Overall Study | Death | 6 | 8 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 53 | 72 |
Baseline characteristics
| Characteristic | Total | Budesonide | Symbicort |
|---|---|---|---|
| Age, Continuous | 43.5 Years STANDARD_DEVIATION 17.3 | 43.5 Years STANDARD_DEVIATION 17.3 | 43.4 Years STANDARD_DEVIATION 17.4 |
| Gender Female | 7669 Participants | 3820 Participants | 3849 Participants |
| Gender Male | 4024 Participants | 2027 Participants | 1997 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 432 Participants | 207 Participants | 225 Participants |
| Race/Ethnicity, Customized Asian | 1755 Participants | 907 Participants | 848 Participants |
| Race/Ethnicity, Customized Black/African American | 797 Participants | 401 Participants | 396 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 6 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 650 Participants | 326 Participants | 324 Participants |
| Race/Ethnicity, Customized White | 8053 Participants | 4003 Participants | 4050 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 5,846 | 0 / 5,847 |
| serious Total, serious adverse events | 125 / 5,846 | 123 / 5,847 |
Outcome results
Primary
Number of Participants Experiencing an Event Included in the Definition of Asthma Exacerbation
Number of participants experiencing an event included in the definition of asthma exacerbation. An asthma exacerbation was defined as a deterioration of asthma requiring systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency room visit due to asthma that required systemic corticosteroids. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated.
Time frame: Up to 26 weeks
Population: The On treatment Analysis set comprised of all randomized patients and included data that corresponded to each patient's period of exposure to study drug plus 7 days after the last date of study drug treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Symbicort | Number of Participants Experiencing an Event Included in the Definition of Asthma Exacerbation | 539 Participants |
| Budesonide | Number of Participants Experiencing an Event Included in the Definition of Asthma Exacerbation | 633 Participants |
p-value: 0.00295% CI: [0.745, 0.937]Regression, Cox
Primary
Number of Participants Experiencing an Event in the Composite Endpoint (Asthma-related Death, Asthma-related Intubation or Asthma-related Hospitalization)
Number of participants experiencing an event in the composite endpoint (asthma-related death, asthma-related intubation or asthma-related hospitalization), using events adjudicated and confirmed by the Joint Adjudication Committee. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated.
Time frame: Up to 27 weeks
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Symbicort | Number of Participants Experiencing an Event in the Composite Endpoint (Asthma-related Death, Asthma-related Intubation or Asthma-related Hospitalization) | 43 Participants |
| Budesonide | Number of Participants Experiencing an Event in the Composite Endpoint (Asthma-related Death, Asthma-related Intubation or Asthma-related Hospitalization) | 40 Participants |
95% CI: [0.698, 1.65]Regression, Cox
Secondary
Asthma Control Questionnaire (ACQ6)
The outcome variable for ACQ6 was the difference between the average of values recorded during the treatment period (day 28, day 84 and day 182) and the baseline measure. Analysis of covariance (ANCOVA) model, including the fixed factors of treatment and strata by incoming control/asthma treatment and baseline ACQ6 as covariate was used to compare Symbicort and budesonide. The asthma control questionnaire, ACQ6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions.
Time frame: baseline, day 28, day 84, day 182
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug with at least one post-baseline ACQ6 score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Symbicort | Asthma Control Questionnaire (ACQ6) | -0.70 ACQ6 overall score change from baseline | Standard Error 0.01 |
| Budesonide | Asthma Control Questionnaire (ACQ6) | -0.62 ACQ6 overall score change from baseline | Standard Error 0.01 |
p-value: <0.00195% CI: [-0.1, -0.06]ANCOVA
Secondary
Mean Number of Puffs of Rescue Medication Per 24 Hours
Mean number of puffs of rescue medication per day (24 hours) during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide.
Time frame: Daily up to 26 weeks
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug and had at least one entry of diary data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Symbicort | Mean Number of Puffs of Rescue Medication Per 24 Hours | 0.8 Inhalations/day | Standard Error 0 |
| Budesonide | Mean Number of Puffs of Rescue Medication Per 24 Hours | 0.9 Inhalations/day | Standard Error 0 |
p-value: <0.00195% CI: [-0.2, -0.1]ANOVA
Secondary
Number of Participants Experiencing Discontinuation of Investigational Product Due to a Protocol Defined Asthma Exacerbation
Number of participants experiencing discontinuation of investigational product due to a protocol defined asthma exacerbation. An asthma exacerbation was defined as a deterioration of asthma requiring systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency room visit due to asthma that required systemic corticosteroids. Cox proportional hazards model with terms for randomized treatment and strata for incoming control/asthma treatment was used to compare Symbicort and budesonide. Hazard ratios and 95% confidence intervals were estimated.
Time frame: Up to 26 weeks
Population: The On treatment Analysis set comprised of all randomized patients and included data that corresponded to each patient's period of exposure to study drug plus 7 days after the last date of study drug treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Symbicort | Number of Participants Experiencing Discontinuation of Investigational Product Due to a Protocol Defined Asthma Exacerbation | 53 Participants |
| Budesonide | Number of Participants Experiencing Discontinuation of Investigational Product Due to a Protocol Defined Asthma Exacerbation | 71 Participants |
p-value: 0.09595% CI: [0.518, 1.055]Regression, Cox
Secondary
Percent of Days With Activity Limitation Due to Asthma
Percent of days with activity limitation due to asthma during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide.
Time frame: Daily up to 26 weeks
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug. The analysis set comprises of all patients with at least one day with asthma symptoms, i.e. the denominator is the number of days with asthma symptoms.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Symbicort | Percent of Days With Activity Limitation Due to Asthma | 19.7 Percentage of days | Standard Error 0.4 |
| Budesonide | Percent of Days With Activity Limitation Due to Asthma | 19.1 Percentage of days | Standard Error 0.4 |
p-value: 0.27295% CI: [-0.5, 1.7]ANOVA
Secondary
Percent of Days With no Asthma Symptoms
Percent of days with no asthma symptoms during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide.
Time frame: Daily up to 26 weeks
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug and had at least one entry of diary data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Symbicort | Percent of Days With no Asthma Symptoms | 81.1 Percentage of days | Standard Error 0.4 |
| Budesonide | Percent of Days With no Asthma Symptoms | 76.8 Percentage of days | Standard Error 0.4 |
p-value: <0.00195% CI: [3.3, 5.4]ANOVA
Secondary
Percent of Nights With Awakening(s) Due to Asthma
Percent of nights with awakening(s) due to asthma during the randomized treatment period. Analysis of variance (ANOVA) model including the fixed factors of treatment and strata by incoming control/asthma treatment was used to compare Symbicort and budesonide.
Time frame: Daily up to 26 weeks
Population: Full analysis set (FAS) population comprised of all patients randomized to study drug and had at least one entry of diary data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Symbicort | Percent of Nights With Awakening(s) Due to Asthma | 4.0 Percentage of nights | Standard Error 0.2 |
| Budesonide | Percent of Nights With Awakening(s) Due to Asthma | 4.7 Percentage of nights | Standard Error 0.2 |
p-value: 0.00495% CI: [-1, -0.2]ANOVA