Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, arterial stiffness, Computed Tomography, pulse wave velocity, Pulse wave analysis
Brief summary
The purpose of this study is to evaluate in patients with Chronic Obstructive Pulmonary Disease (COPD) if Advair DISKUS™ 250/50mcg BID modifies arterial stiffness which is a measure associated with risk of heart disease.
Detailed description
This is a multicenter, randomized, double-blind, placebo controlled study to evaluate the effect of Fluticasone Propionate/Salmeterol DISKUS 250/50mcg (FSC) BID on arterial stiffness in COPD subjects. Following a 1 to 14 day run-in period, approximately 250 subjects will be randomly assigned to double-blind treatment for 12 weeks. After the 12 week treatment period, subjects in both treatment arms will receive open label Tiotropium bromide Handihaler18mcg (Tio)QD for 4 weeks in addition to their continued study drug (either FSC250/50 or placebo). The primary measure of efficacy is Pulse Wave Velocity (PWV) at Endpoint. Secondary efficacy measures include Augmentation Index (AIx), Biomarkers of cardiovascular disease, measures of lung function. (e.g. FEV1). Safety will be assessed through the collection of adverse events and COPD exacerbations. Exploratory endpoints include the effect of Tiotropium on PWV and AIx when added to placebo or FSC. Treatment groups will be stratified based on current smoking status. There will be a total of 6 study visits (screening, randomization, and after 4, 8, 12 and 16 weeks of treatment). A follow-up phone contact for collection of adverse event and pregnancy information (if applicable) will be conducted approximately 14 days following the last study visit.
Interventions
DRUGADVAIR DISKUS™ 250/50mcg
ADVAIR DISKUS™ 250/50mcg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. ADVAIR DISKUS™ 250/50mcg is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.
OTHERPlacebo
COPD subjects-Placebo DISKUS
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent obtained from the subject and/or subject's legally acceptable representative prior to study participation. * Males or females greater then or equal to 50 years of age. * A post-albuterol FEV1/FVC ratio of \< or equal to 0.70 * A post-albuterol FEV1 \< 80% of predicted normal. * Patients can be current or fomer smoker and must have a cigarette smoking history of \> greater then or equal to 10 pack-years .
Exclusion criteria
* A current diagnosis of asthma * A body mass index (BMI) of \> or equal to 35kg/m2 * A respiratory diagnosis other than COPD (e.g., lung cancer, bronchiectasis, sarcoidosis, tuberculosis, lung fibrosis).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | Baseline and the 12-Week Endpoint (up to Week 12) | The 12-week Endpoint is defined as the last scheduled measurement of PWV during the 12-week double-blind treatment period (from Visits 3-5; Weeks 4, 8, and 12, respectively), and Baseline is defined as the PWV measure from Visit 2 (Randomization). Change from Baseline was calculated as the Endpoint value minus the Baseline Value. PWV is used as a measure of arterial stiffness, which is a measure of the cushioning functioning of major vessels like the aorta. The velocity of the PW along an artery is dependent on the stiffness of that artery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | Baseline and the 12-Week Endpoint (up to Week 12) | AIx is a surrogate measure of peripheral (not aortic) arterial resistance and is measured by analysis of the pulse wave at the radial artery. AIx = (\[delta P/Pulse Pressure\] x 100); delta P is defined by a notch near the peak of the pulse wave. Change from Baseline was calculated as the Endpoint value minus the Baseline Value. |
| Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | Baseline and the 12-Week Endpoint (up to Week 12) | FEV1 is a measure of air flow via spirometry. Change from Baseline was calculated as the Endpoint value minus the Baseline Value. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FSC DISKUS 250/50 mcg Fluticasone Propionate/Salmeterol (FSC) DISKUS 250/50 micrograms (mcg) twice daily. At Visit 5 (Week 12), participants received open-label Tiotropium inhalation capsules 18 mcg per dose via Handihaler inhalation device. | 123 |
| Matching Placebo Matching placebo DISKUS twice daily. At Visit 5 (Week 12), participants received open-label Tiotropium inhalation capsules 18 mcg per dose via Handihaler inhalation device. | 126 |
| Total | 249 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 12 |
| Overall Study | Investigator Discretion | 2 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Participant Withdrew Consent | 4 | 4 |
| Overall Study | Protocol Violation | 11 | 11 |
Baseline characteristics
| Characteristic | FSC DISKUS 250/50 mcg | Matching Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 8.92 | 63.5 Years STANDARD_DEVIATION 7.88 | 63.5 Years STANDARD_DEVIATION 8.4 |
| Gender Female | 55 Participants | 52 Participants | 107 Participants |
| Gender Male | 68 Participants | 74 Participants | 142 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 7 participants | 9 participants | 16 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 114 participants | 114 participants | 228 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 123 | 7 / 126 |
| serious Total, serious adverse events | 8 / 123 | 8 / 126 |
Outcome results
Primary
Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint
The 12-week Endpoint is defined as the last scheduled measurement of PWV during the 12-week double-blind treatment period (from Visits 3-5; Weeks 4, 8, and 12, respectively), and Baseline is defined as the PWV measure from Visit 2 (Randomization). Change from Baseline was calculated as the Endpoint value minus the Baseline Value. PWV is used as a measure of arterial stiffness, which is a measure of the cushioning functioning of major vessels like the aorta. The velocity of the PW along an artery is dependent on the stiffness of that artery.
Time frame: Baseline and the 12-Week Endpoint (up to Week 12)
Population: Intent-to-Treat (ITT) Population: all participants who were randomized to study drug. The number analyzed at baseline is different from that at the 12-week endpoint due to participant withdrawal. Data are missing for some participants in the ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | Baseline, n=118, 122 | 10.06 meters per second (m/s) | Standard Error 0.26 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | 12-Week Endpoint, n=113, 110 | 9.83 meters per second (m/s) | Standard Error 0.24 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | Change from Baseline | -0.24 meters per second (m/s) | Standard Error 0.194 |
| Matching Placebo | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | Baseline, n=118, 122 | 9.87 meters per second (m/s) | Standard Error 0.25 |
| Matching Placebo | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | 12-Week Endpoint, n=113, 110 | 9.95 meters per second (m/s) | Standard Error 0.26 |
| Matching Placebo | Mean Change From Baseline in Aortic Pulse Wave Velocity (aPWV) at the 12-Week Endpoint | Change from Baseline | 0.13 meters per second (m/s) | Standard Error 0.157 |
p-value: 0.06595% CI: [-0.88, 0.03]ANCOVA
Secondary
Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint
AIx is a surrogate measure of peripheral (not aortic) arterial resistance and is measured by analysis of the pulse wave at the radial artery. AIx = (\[delta P/Pulse Pressure\] x 100); delta P is defined by a notch near the peak of the pulse wave. Change from Baseline was calculated as the Endpoint value minus the Baseline Value.
Time frame: Baseline and the 12-Week Endpoint (up to Week 12)
Population: ITT Population. The number analyzed at baseline is different from that at the 12-week endpoint due to participant withdrawal. Data are missing for some participants in the ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | Baseline, n=121, 122 | 27.9 % of total height of peak pulse pressure | Standard Error 0.83 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | 12-Week Endpoint, n=114, 111 | 27.2 % of total height of peak pulse pressure | Standard Error 0.82 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | Change from Baseline | -0.7 % of total height of peak pulse pressure | Standard Error 0.66 |
| Matching Placebo | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | Baseline, n=121, 122 | 27.8 % of total height of peak pulse pressure | Standard Error 0.83 |
| Matching Placebo | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | 12-Week Endpoint, n=114, 111 | 27.6 % of total height of peak pulse pressure | Standard Error 0.82 |
| Matching Placebo | Mean Change From Baseline in Augmentation Index (AIx) at the 12-Week Endpoint | Change from Baseline | -0.4 % of total height of peak pulse pressure | Standard Error 0.72 |
p-value: 0.46995% CI: [-2.3, 1.1]ANCOVA
Secondary
Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint
FEV1 is a measure of air flow via spirometry. Change from Baseline was calculated as the Endpoint value minus the Baseline Value.
Time frame: Baseline and the 12-Week Endpoint (up to Week 12)
Population: ITT Population. The number analyzed at baseline is different from that at the 12-week endpoint due to participant withdrawal. Data are missing for some participants in the ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | Baseline, n=123, 125 | 1444 milliliters | Standard Error 53.7 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | 12-Week Endpoint, n=105, 102 | 1588 milliliters | Standard Error 59.6 |
| FSC DISKUS 250/50 mcg | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | Change from Baseline | 136 milliliters | Standard Error 22 |
| Matching Placebo | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | Baseline, n=123, 125 | 1480 milliliters | Standard Error 60.1 |
| Matching Placebo | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | 12-Week Endpoint, n=105, 102 | 1500 milliliters | Standard Error 61.6 |
| Matching Placebo | Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at the 12-Week Endpoint | Change from Baseline | -3 milliliters | Standard Error 30.4 |
p-value: <0.00195% CI: [57, 197]ANCOVA