Asthma
Conditions
Keywords
asthmatic children, Symbicort, Foradil
Brief summary
This purpose of the study is to investigate the bronchodilating effects of 3 different dosages of formoterol given in combination with budesonide as Symbicort pMDI.
Detailed description
A Phase 2, randomized, blinded, 5-period cross-over, placebo and active controlled, multicenter, dose-finding study comparing single doses of formoterol 2.25 µg, 4.5 µg, and 9 µg delivered via Symbicort pMDI and Foradil® 12 µg evaluating the relative bronchodilating effects and safety in children.
Interventions
DRUG80/2.25 μg Symbicort pMDI
inhalation
DRUG80/4.5 μg Symbicort pMDI
inhalation
DRUGForadil Aerolizer 12 μg
inhalation
DRUG40 μg budesonide HFA pMDI
inhalation
DRUGplacebo HFA pMDI
inhalation
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Has a documented clinical diagnosis of asthma for at least 6 months prior to Visit 1 * Has a FEV1 measured at least 6 hours after the last dose of inhaled, short-acting β2-agonist (SABA) and at least 48 hours after the last dose of inhaled long-acting β2-agonist of =60% and =85% of predicted normal. * Demonstrated reversibility of FEV1 of =15% from pre short acting beta agonist level within 15 to 30 minutes after administration of a standard dose of short acting beta agonist
Exclusion criteria
* Has been hospitalized for \>24 hours at least once or required emergency treatment or urgent care visit more than once for an asthma-related condition during the 6 months prior to Visit 1 * Has required treatment with systemic corticosteroids (eg, oral, parenteral, or rectal) for any reason within the 12 weeks prior to Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose | Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was obtained from the full expiratory flow-volume-time curve. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. Twelve-hour serial FEV1 was calculated through an AUC determination and then divided by time, so that the final value is expressed in liters. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 at 12 Hours After Study Medication Inhalation | 12 hours after dosing | Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. The FEV1 value at 12 hours after dosing was taken as the 12-hour measurement (720 minutes) from the serial spirometry. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0. |
| Maximal FEV1 During the 12-hour Study Period | at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose | Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. The maximum FEV1 value was defined as the largest observed FEV1 value recorded during each 12-hour serial spirometry procedure. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0. |
| Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug | 0 to 12 hours | The amount of formoterol excreted unchanged in urine over the 12-hour period after administration \[Ae(0-12h)\] was calculated from the concentration of formoterol in urine multiplied by the total volume of urine collected. Volume was determined from the weight of the collected urine times an assumed urine density of 1020 g/L. The data for six patients who did not have measurable formoterol in their urine on the Foradil 12 μg treatment day was excluded from the analysis. All other urine concentrations below the lower limit of quantification were set to zero. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0. |
Countries
Bulgaria, Czechia, Hungary, Poland, South Africa, United States
Participant flow
Recruitment details
This multicenter study was conducted in Europe and the United States between 7 October 2010 and 3 January 2012.
Pre-assignment details
The study consisted of a screening visit, an enrolment visit, a 1- to 2-week run-in (standardization) period, randomization at Visit 3, and 4 further visits (Visits 4-7)separated by approximately 7-day (minimum 3 days; maximum 14 days) wash-out (stabilization) periods. Subjects received 1 of 5 single-dose treatments at Visits 3-7, in random order.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Patients All randomized patients | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Washout After BUD 160/FM 2.25 (7 Days) | Withdrawal by Subject | 1 |
| Washout After BUD 160/FM 4.5 (7 Days) | Adverse Event | 1 |
| Washout After BUD 160/FM 9.0 (7 Days) | Adverse Event | 1 |
| Washout After BUD 160/FM 9.0 (7 Days) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Randomized Patients |
|---|---|
| Age Continuous | 9.2 years STANDARD_DEVIATION 1.79 |
| Age, Customized >=6 to <8 years | 11 participants |
| Age, Customized >=8 to < 12 years | 43 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 54 | 1 / 53 | 5 / 53 | 2 / 51 | 0 / 50 |
| serious Total, serious adverse events | 0 / 54 | 0 / 53 | 0 / 53 | 0 / 51 | 0 / 50 |
Outcome results
Primary
Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1)
Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was obtained from the full expiratory flow-volume-time curve. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. Twelve-hour serial FEV1 was calculated through an AUC determination and then divided by time, so that the final value is expressed in liters. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time frame: at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose
Population: Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BUD 160/FM 2.25 | Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | 1.546 liters | Standard Error 0.0097 |
| BUD 160/FM 4.5 | Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | 1.594 liters | Standard Error 0.0099 |
| BUD 160/FM 9.0 | Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | 1.603 liters | Standard Error 0.0099 |
| BUD 160 | Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | 1.489 liters | Standard Error 0.0101 |
| BUD 160/ Foradil 12.0 | Average 12 Hour Forced Expiratory Volume in 1 Second (FEV1) | 1.603 liters | Standard Error 0.0101 |
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [0.087, 0.142]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [0.078, 0.133]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000195% CI: [0.03, 0.085]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.522395% CI: [-0.036, 0.018]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000195% CI: [-0.084, -0.029]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000795% CI: [-0.075, -0.02]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [-0.142, -0.086]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000195% CI: [-0.084, -0.028]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.539495% CI: [-0.036, 0.019]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.986395% CI: [-0.027, 0.028]ANCOVA
Secondary
FEV1 at 12 Hours After Study Medication Inhalation
Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. The FEV1 value at 12 hours after dosing was taken as the 12-hour measurement (720 minutes) from the serial spirometry. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time frame: 12 hours after dosing
Population: Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BUD 160/FM 2.25 | FEV1 at 12 Hours After Study Medication Inhalation | 1.641 liters | Standard Error 0.0175 |
| BUD 160/FM 4.5 | FEV1 at 12 Hours After Study Medication Inhalation | 1.692 liters | Standard Error 0.0177 |
| BUD 160/FM 9.0 | FEV1 at 12 Hours After Study Medication Inhalation | 1.731 liters | Standard Error 0.0177 |
| BUD 160 | FEV1 at 12 Hours After Study Medication Inhalation | 1.626 liters | Standard Error 0.0181 |
| BUD 160/ Foradil 12.0 | FEV1 at 12 Hours After Study Medication Inhalation | 1.709 liters | Standard Error 0.0182 |
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [0.056, 0.155]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.009295% CI: [0.017, 0.116]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.550995% CI: [-0.035, 0.065]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.116395% CI: [-0.088, 0.01]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000495% CI: [-0.14, -0.041]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.0495% CI: [-0.1, -0.002]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.001195% CI: [-0.133, -0.034]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.007795% CI: [-0.118, -0.018]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.495795% CI: [-0.067, 0.033]ANCOVA
Comparison: Factors in the ANCOVA model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.3895% CI: [-0.027, 0.071]ANCOVA
Secondary
Maximal FEV1 During the 12-hour Study Period
Pulmonary function tests consisted of 3 forced expiratory maneuvers in which the patient expired forcefully from total lung capacity to residual volume, recorded using a spirometer. FEV1 was measured at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post administration of randomized study medication. The maximum FEV1 value was defined as the largest observed FEV1 value recorded during each 12-hour serial spirometry procedure. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time frame: at 3, 9, 15, 60, 120, 180, 240, 360, 480, 600 and 720 minutes postdose
Population: Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BUD 160/FM 2.25 | Maximal FEV1 During the 12-hour Study Period | 1.833 liters | Standard Error 0.0119 |
| BUD 160/FM 4.5 | Maximal FEV1 During the 12-hour Study Period | 1.889 liters | Standard Error 0.012 |
| BUD 160/FM 9.0 | Maximal FEV1 During the 12-hour Study Period | 1.884 liters | Standard Error 0.012 |
| BUD 160 | Maximal FEV1 During the 12-hour Study Period | 1.777 liters | Standard Error 0.0123 |
| BUD 160/ Foradil 12.0 | Maximal FEV1 During the 12-hour Study Period | 1.892 liters | Standard Error 0.0123 |
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [0.073, 0.14]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [0.078, 0.146]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.001195% CI: [0.023, 0.09]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.758995% CI: [-0.028, 0.039]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.003595% CI: [-0.084, -0.017]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.001195% CI: [-0.089, -0.022]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: <0.000195% CI: [-0.149, -0.081]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.000895% CI: [-0.092, -0.024]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.858295% CI: [-0.037, 0.031]ANCOVA
Comparison: Factors in the Analysis of Covariance model included: patient, visit, treatment, and the covariate pre-dose FEV1 from each visit.p-value: 0.627695% CI: [-0.042, 0.025]ANCOVA
Secondary
Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug
The amount of formoterol excreted unchanged in urine over the 12-hour period after administration \[Ae(0-12h)\] was calculated from the concentration of formoterol in urine multiplied by the total volume of urine collected. Volume was determined from the weight of the collected urine times an assumed urine density of 1020 g/L. The data for six patients who did not have measurable formoterol in their urine on the Foradil 12 μg treatment day was excluded from the analysis. All other urine concentrations below the lower limit of quantification were set to zero. One subject was incorrectly administered BUD 160/ formoterol (FM) 9.0 rather than BUD 160/ Foradil 12.0 at Period 4. Hence this subject is included in the Efficacy Analysis Set, but not the Safety Analysis Set for BUD 160/ Foradil 12.0.
Time frame: 0 to 12 hours
Population: Efficacy analysis set including all patients who were randomized (defined as having a randomization code recorded on the demography case report form), received at least one dose of study medication, and contributed sufficient data for at least one efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BUD 160/FM 2.25 | Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug | 192.0 pmol |
| BUD 160/FM 4.5 | Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug | 366.3 pmol |
| BUD 160/FM 9.0 | Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug | 740.6 pmol |
| BUD 160 | Urinary Excretion of Formoterol During the 12 Hours Following Inhalation of Study Drug | 658.7 pmol |
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: <0.000195% CI: [0.393, 0.7]ANOVA
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: <0.000195% CI: [0.194, 0.347]ANOVA
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: <0.000195% CI: [0.214, 0.396]ANOVA
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: <0.000195% CI: [0.371, 0.659]ANOVA
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: 0.000295% CI: [0.409, 0.755]ANOVA
Comparison: Factors in the ANOVA model included: patient, period and treatment.p-value: 0.451295% CI: [0.827, 1.528]ANOVA