Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Respiratory, COPD, O2 Consumption
Brief summary
A Phase IV study evaluating changes in oxygen consumption and cardiac function in Subjects with Chronic obstructive pulmonary disease (COPD) with resting hyperinflation after administration of Symbicort pMDI 160/4.5 μg.
Detailed description
Patients with moderate/severe COPD are known to have static hyperinflation and to develop dynamic hyperinflation during exercise. Treatment with inhaled long-acting beta agonists and combination of the long-acting beta agonist (LABA), formoterol and the inhaled corticosteroid, budesonide has been shown to improve IC and decrease lung hyperinflation. In a similar previous pilot single centre study with budesonide/formoterol (Symbicort®) the analysis of cardiac outcomes demonstrated a decrease in maximum volume of oxygen (VO2) compared to placebo. Findings suggested that the use of Symbicort can decrease the cost of breathing and therefore reduce the cardiac demand experienced by COPD patients with hyperinflation at rest. The aim of this study is to investigate whether Symbicort therapy can decrease resting VO2 by decreasing static lung hyperinflation in subjects with COPD and to evaluate changes in cardiac function.
Interventions
DRUGBudesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg Inhalation aerosol
Subjects will receive a single dose (2 inhalations) of Symbicort pMDI 160/4.5 μg (2 inhalations; total dosage 320/9.0 μg) or placebo (with a spacer) in a cross-over design (a total of 2 doses of Symbicort and 2 doses of placebo over the duration of the study), and assessments will be made before and after dosing at specified timepoints
DRUGMatching Placebo pMDI 160/4.5 μg
Placebo will be given according at the same dose and schedule as the active comparator - cross-over design.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Signing of the informed consent form (ICF) prior to any study specific procedures, including withholding of medications. 2. Male or female, aged 40 to 80 years, inclusive, at Screening (Visit 1). 3. Has a clinical diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014 guidelines with a post bronchodilator FEV1/FVC \<0.7 at Screening (Visit 1). 4. Has a post-bronchodilator FEV1 ≤65% of predicted value at Screening (Visit 1). National Health and Nutrition Examination Survey (NHANES) predicted normal standards will be used for all subjects. 5. Has an increase in IC of \>10% after the administration of 1 inhalation of open-label Symbicort pMDI administered with a spacer at Screening (Visit 1). 6. Has a cigarette smoking history of more than 10 pack-years (number of cigarettes smoked per day × number of years smoked)/20). 7. Be able to understand and comply with study requirements, as judged by the Investigator.
Exclusion criteria
1. Subject is an employee or relative of an employee involved in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 2. Previous enrollment or randomization in this study. 3. Participation in another clinical study with an investigational product (IP) during the last 30 days prior to Screening (Visit 1). 4. Subjects who are unable to discontinue their regular chronic COPD medications (including LAMAs and/or LABA/ICS) and/or who are unable or unwilling to comply with study requirements. 5. Subjects who are taking uLABAs (indacaterol, vilanterol) or uLABA-containing products. 6. Subjects who are taking PDE-4 inhibitors (roflumilast). 7. Subjects who are taking oral corticosteroids on a chronic, regular basis. 8. Subjects using daytime oxygen therapy. 9. Subjects who are currently pregnant (confirmed with positive pregnancy test) or breast feeding. 10. History of respiratory tract infection (including the upper respiratory tract) and/or pulmonary exacerbation within 6 weeks prior to Screening (Visit 1). 11. Pulmonary resection or lung volume reduction surgery within 12 months prior to Screening (Visit 1), or history of lung transplantation, or, in the Investigator's opinion, the subject may need thoracotomy or other lung surgery during the study. 12. History or current diagnosis of asthma and/or alpha 1 anti-trypsin deficiency. 13. Known active tuberculosis. 14. History of interstitial lung or massive pulmonary thromboembolic disease. 15. History of bronchiectasis secondary to respiratory diseases other than COPD (eg, cystic fibrosis, Kartagener's syndrome, etc). 16. Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the results of the study, or may affect the subject's ability to participate in the study. 17. Recent (within 12 months prior to Screening \[Visit 1\]) history of myocardial infarction, recent history of heart failure (New York Heart Association \[NYHA\] class III and IV, pulmonary edema, and/or cardiac arrhythmia. 18. Previous or current history of lung cancer. 19. History of cancer (within 5 years prior to Visit 1), except for non-metastatic, non melanoma skin cancer. 20. Subjects who cannot perform spirometry manuevers or tolerate body plethysmography. 21. Subjects with known hypersensitivity to Symbicort, its monocomponents (budesonide or formoterol), or its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Consumption (VO2; Obtained Via a Metabolic Cart) | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter HR | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and IC (using an slow vital capacity \[SVC\] maneuver; IC/total lung capacity \[TLC\] will be used as a measure of resting hyperinflation). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change in Vt/Ti | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in mean inspiratory flow (tidal volume \[Vt\]/inspiratory time \[Ti\]). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in the Modified Borg Scale for Dyspnea | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). Modified Borg scale for dyspnea was self-administered at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21). The Borg scale is a 1-item instrument through which a subject reports dyspnea symptoms on a scale of 0-10 to quantify the intensity of dyspnea (where 10 is most intense). |
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter VCO2 | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Pulse (Defined as VO2/Heart Rate [HR]; VO2 is Obtained Via a Metabolic Cart; Used as a Surrogate for Stroke Volume) | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change in RR | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change in Ti/Ttot | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in fractional inspiratory time (Ti/total cycle time \[Ttot\]). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change in Vt | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in tidal volume (Vt). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change in Ve | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in minute ventilation (Ve). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Spirometry. | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | FEV1/FVC. For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
| Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter SaO2 | Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported. | For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 5 sites in the United States (US) between 25 August 2015 and 12 August 2016.
Pre-assignment details
This was a Phase 4, randomized, double-blind, multi-center, placebo-controlled, 2 way cross over study to evaluate changes in oxygen consumption and cardiac function in COPD patients with resting hyperinflation after administration of Symbicort pMDI. The study consisted of 5 site visits and 1 phone visit for a total study duration of 6 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Over All | 51 |
| Total | 51 |
Baseline characteristics
| Characteristic | Over All |
|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 8.32 |
| Age, Customized <50 | 3 Participants |
| Age, Customized >=50 - <65 | 27 Participants |
| Age, Customized >=65 | 21 Participants |
| Race/Ethnicity, Customized Black Or African American | 13 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 37 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 51 | 11 / 51 |
| serious Total, serious adverse events | 0 / 51 | 1 / 51 |
Outcome results
Primary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Consumption (VO2; Obtained Via a Metabolic Cart)
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Consumption (VO2; Obtained Via a Metabolic Cart) | 11.366 mL/min |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Consumption (VO2; Obtained Via a Metabolic Cart) | 1.252 mL/min |
p-value: 0.00795% CI: [2.943, 17.286]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter HR
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter HR | -2.481 ΔHR: beats/min |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter HR | -2.831 ΔHR: beats/min |
Comparison: ΔHRp-value: 0.60995% CI: [-1.018, 1.719]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter SaO2
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter SaO2 | 0.422 SaO2: % |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter SaO2 | 0.181 SaO2: % |
Comparison: ΔSaO2p-value: 0.33395% CI: [-0.255, 0.738]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter VCO2
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter VCO2 | 5.994 ΔVCO2: mL/min |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Gas Exchange Parameter VCO2 | -4.251 ΔVCO2: mL/min |
Comparison: ΔVCO2p-value: 0.01195% CI: [2.469, 18.021]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Pulse (Defined as VO2/Heart Rate [HR]; VO2 is Obtained Via a Metabolic Cart; Used as a Surrogate for Stroke Volume)
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Pulse (Defined as VO2/Heart Rate [HR]; VO2 is Obtained Via a Metabolic Cart; Used as a Surrogate for Stroke Volume) | 0.256 mL/min/beats/min |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Oxygen Pulse (Defined as VO2/Heart Rate [HR]; VO2 is Obtained Via a Metabolic Cart; Used as a Surrogate for Stroke Volume) | 0.168 mL/min/beats/min |
p-value: 0.11195% CI: [-0.021, 0.196]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Spirometry.
FEV1/FVC. For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: ΔFEV1/FVC calculated as ratio.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Spirometry. | 0.017 ratio |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in Spirometry. | -0.002 ratio |
Comparison: ΔFEV1/FVCp-value: 0.00795% CI: [0.005, 0.033]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry.
Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and IC (using an slow vital capacity \[SVC\] maneuver; IC/total lung capacity \[TLC\] will be used as a measure of resting hyperinflation). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔFEV1 | 0.187 FEV1: L; ΔFVC: L; ΔIC: L |
| Symbicort pMDI | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔFVC | 0.259 FEV1: L; ΔFVC: L; ΔIC: L |
| Symbicort pMDI | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔIC | 0.256 FEV1: L; ΔFVC: L; ΔIC: L |
| Placebo | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔFEV1 | -0.004 FEV1: L; ΔFVC: L; ΔIC: L |
| Placebo | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔFVC | -0.052 FEV1: L; ΔFVC: L; ΔIC: L |
| Placebo | Change From Pre-dose (Visit 2)to Post-dose (Visit 5) Assessment in Spirometry. | ΔIC | -0.024 FEV1: L; ΔFVC: L; ΔIC: L |
Comparison: ΔFEV1p-value: <0.00195% CI: [0.15, 0.233]Mixed Models Analysis
Comparison: ΔFVCp-value: <0.00195% CI: [0.236, 0.388]Mixed Models Analysis
Comparison: ΔICp-value: <0.00195% CI: [0.218, 0.342]Mixed Models Analysis
Secondary
Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in the Modified Borg Scale for Dyspnea
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo). Modified Borg scale for dyspnea was self-administered at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21). The Borg scale is a 1-item instrument through which a subject reports dyspnea symptoms on a scale of 0-10 to quantify the intensity of dyspnea (where 10 is most intense).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in the Modified Borg Scale for Dyspnea | -0.452 units on a scale |
| Placebo | Change From Pre-dose (Visit 2) to Post-dose (Visit 5) Assessment in the Modified Borg Scale for Dyspnea | -0.248 units on a scale |
p-value: 0.10695% CI: [-0.454, 0.045]Mixed Models Analysis
Secondary
Change in RR
For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: ΔRR: breaths/min
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change in RR | -0.193 breaths/min |
| Placebo | Change in RR | -0.430 breaths/min |
Comparison: ΔRRp-value: 0.48495% CI: [-0.439, 0.913]Mixed Models Analysis
Secondary
Change in Ti/Ttot
Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in fractional inspiratory time (Ti/total cycle time \[Ttot\]). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: ΔTi/Ttot is measured as a ratio.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change in Ti/Ttot | 0.012 ratio |
| Placebo | Change in Ti/Ttot | -0.004 ratio |
Comparison: ΔTi/Ttotp-value: 0.11395% CI: [-0.004, 0.036]Mixed Models Analysis
Secondary
Change in Ve
Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in minute ventilation (Ve). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: Units of measure: ΔVe: mL/min.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change in Ve | 838.232 mL/min |
| Placebo | Change in Ve | -23.924 mL/min |
Comparison: ΔVep-value: <0.00195% CI: [439.817, 1284.496]Mixed Models Analysis
Secondary
Change in Vt
Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in tidal volume (Vt). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: Units of measure: ΔVt: mL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change in Vt | 71.904 mL |
| Placebo | Change in Vt | 14.281 mL |
Comparison: ΔVtp-value: <0.00195% CI: [29.701, 85.546]Mixed Models Analysis
Secondary
Change in Vt/Ti
Change from pre-dose (Visit 2) to post-dose (Visit 5) assessment in mean inspiratory flow (tidal volume \[Vt\]/inspiratory time \[Ti\]). For all outcome measures, treatment group estimates are LS Means across visits (change between 2 or more time points, calculated as the value at the later time point minus the value at the earlier time point, e.g. LS means across visits up to Visit 5 minus pre-dose Visit 2 value). Estimate for difference = LS Mean (Symbicort pMDI 160mcg/4.5ug) - LS Mean (placebo).
Time frame: Assessment (60 minutes pre and post dose) at Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 21); change from baseline pre-dose to Day 21 post-dose reported.
Population: Units of measure: Vt/Ti: mL/sec
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | Change in Vt/Ti | 26.533 mL/sec |
| Placebo | Change in Vt/Ti | 3.217 mL/sec |
Comparison: ΔVT/Tip-value: 0.02195% CI: [3.723, 42.907]Mixed Models Analysis