Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The purpose of the study is to investigate the effect of fluticasone furoate/vilanterol Inhalation Powder on arterial stiffness compared with placebo and vilanterol over a 24-week treatment period in subjects with COPD and aortic pulse wave velocity of 11.0 m/s or above.
Interventions
Inhaled corticosteroid/long acting beta-agonist
DRUGVilanterol
Inhaled long acting beta-agonist
DRUGPlacebo
Placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* COPD diagnosis defined by ATS/ERS * Former or current smoker * A measured aortic pulse wave velocity = or \> 11.0 m/s at Screening
Exclusion criteria
* Pregnancy * A current diagnosis of asthma * alpha1-antitrypsin deficiency as the underlying cause of COPD * subjects with other and active respiratory disorders * A cardiovascular event occurred in the 6 months prior to Visit 1 * Current severe heart failure (New York Heart Association Class IV) and have a known ejection fraction of \< 30 % * Clinical significant and uncontrolled hypertension * Abnormal and clinical significant 12-lead ECG findings at Visit 1 * Have lung volume reduction or lung transplantation within 12 months prior to Visit 1 * Poorly controlled COPD: Acute worsening of COPD that is managed by subject with antibiotics or corticosteroids, or requires treatment prescribed by a physician in the 6 weeks prior to Visit 1; or subject needs to be hospitalised due to poorly controlled COPD within 12 weeks prior to Visit 1 * Lower respiratory tract infection that required use of antibiotics within 6 weeks prior to Visit 1 * Participate in the acute phase of a pulmonary rehabilitation within 4 weeks prior to Visit 1 or who will enter the acute phase of pulmonary rehabilitation during the study. * Other diseases or abnormalities in the opinion of the investigator would put safety of the subject at risk through participation; or would affect the safety or efficacy analysis if the disease/condition exacerbated during the study. * subjects with carcinoma has not been in complete remission for at least 5 years. Carcinoma in site of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis. * subjects with a history of hypersensitivity to any of the study medications or components of the inhalation powder. * subjects with a known or suspected history of alcohol or drug abuse within the last 2 years prior to Screening * subjects are medically unable to withhold albuterol or ipratropium for 4 hours prior to spirometry testing at each study visit * subjects are medically unable to stop the 'excluded medications' listed in the protocol * subjects started, discontinued certain medications listed in the protocol or have not been on a stable dose in the past three months prior to Screening, or are not anticipated to remain on a stable dose during the study treatment period. * Long term oxygen therapy requiring \>12 hour per day or a flow rate \> 2 L/min * A body mass index = or \>35 kg/m2 * Fasting lipid level LDL\>3.3 mmol/L, total cholesterol \>5.2 mmol/L, and triglycerides \> 2.24mmol/L * Non-compliance * Questionable validity of consent * Prior use of study medication or other investigational drugs. * Affiliation with investigator site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 24-week Treatment Period (Day 168) | BL to Day 168 | PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of (Eh/2ρR), where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and ρ is the blood density. Change from BL was calculated as the Day 168 value minus the BL value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking history, history of exacerbation strata, geographical region, BL aPWV and interaction terms of BL by visit and treatment by visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From BL in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 168 | BL to Day 168 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry at Screening, Days 1, 28, 84, 126, and 168. BL FEV1 was defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 was defined as the mean of the FEV1 values obtained 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was preformed using a repeated measures model with covariates of visit, treatment, history of exacerbation strata, geographical region, BL FEV1 and interaction terms of BL by visit and treatment by visit. |
| Mean Number of Occasions Rescue Medication [Albuterol (Salbutamol)] Used During a 24-hour Period Averaged Over the Entire 24-week Treatment Period | BL (Week -1), Week 1 to Week 24 | Participants were given daily record cards for daily completion from BL (Week -1) through Week 24 (Visit 6) each morning and prior to taking study medication (i.e., single-blind and double-blind study medication) supplemental medication (albuterol \[salbutamol\] if received) and ipratropium bromide (if received). Participants recorded number of occasions supplemental albuterol/salbutamol (MDI and/or nebules) used over the previous 24 hours and any medical problems that they had experienced and any medication used to treat these medical problems over the previous 24 hours. Analysis was performed using an analysis of covarience (ANCOVA) model with covariates of treatment, BL mean of occasions of rescue medication use (Week -1), history of exacerbation, and geographical region. |
Countries
Germany, Norway, Philippines, South Korea, Thailand, United States
Participant flow
Recruitment details
A total of 3011 participants (par.) were screened, 559 entered the Run-in Period (RIP), of whom 444 were randomized and received at least one dose of study medication; 430 of these were included in the Intent-to-Treat (ITT) Population.
Pre-assignment details
Eligible par. at screening entered a 2-week, single-blind placebo RIP to obtain albuterol (salbutamol) use at Baseline, and to ensure that par.'s COPD was stable at randomization. At the end of the RIP, par. meeting the randomization criteria entered the double-blind treatment period (TP) of 24 weeks (Wk).
Participants by arm
| Arm | Count |
|---|---|
| Placebo QD Participants received placebo QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol) , to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods. | 141 |
| VI 25 µg QD Participants received VI 25 µg inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol), to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods. | 154 |
| FF/VI 100/25 µg QD Participants received FF/VI 100/25 µg inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol) to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods. | 135 |
| Total | 430 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 24-week, Double-blind Treatment Period | Adverse Event | 0 | 8 | 6 | 7 |
| 24-week, Double-blind Treatment Period | Lack of Efficacy-No Sub-Reason | 0 | 2 | 0 | 0 |
| 24-week, Double-blind Treatment Period | Lack of Efficacy-Sub-Reason Exacerbation | 0 | 13 | 13 | 6 |
| 24-week, Double-blind Treatment Period | Lost to Follow-up | 0 | 3 | 0 | 0 |
| 24-week, Double-blind Treatment Period | Physician Decision | 0 | 3 | 1 | 1 |
| 24-week, Double-blind Treatment Period | Protocol-defined Stopping Criteria | 0 | 4 | 3 | 6 |
| 24-week, Double-blind Treatment Period | Protocol Violation | 0 | 4 | 3 | 3 |
| 24-week, Double-blind Treatment Period | Withdrawal by Subject | 0 | 7 | 4 | 1 |
| 2-week, Single-blind Run-In Period | Adverse Event | 1 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Did Not Meet Continuation Criteria | 102 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Lost to Follow-up | 2 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Physician Decision | 1 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Withdrawal by Subject | 9 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo QD | VI 25 µg QD | FF/VI 100/25 µg QD |
|---|---|---|---|---|
| Age, Continuous | 68.5 Years STANDARD_DEVIATION 7.91 | 68.2 Years STANDARD_DEVIATION 8.1 | 68.7 Years STANDARD_DEVIATION 7.69 | 68.5 Years STANDARD_DEVIATION 8.01 |
| Race/Ethnicity, Customized African American/African Heritage | 17 Participants | 7 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 62 Participants | 21 Participants | 23 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian - Mixed Race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 143 Participants | 45 Participants | 51 Participants | 47 Participants |
| Race/Ethnicity, Customized Mixed Race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 203 Participants | 64 Participants | 75 Participants | 64 Participants |
| Sex: Female, Male Female | 89 Participants | 22 Participants | 36 Participants | 31 Participants |
| Sex: Female, Male Male | 341 Participants | 119 Participants | 118 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 145 | 27 / 158 | 34 / 141 |
| serious Total, serious adverse events | 5 / 145 | 12 / 158 | 9 / 141 |
Outcome results
Primary
Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 24-week Treatment Period (Day 168)
PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of (Eh/2ρR), where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and ρ is the blood density. Change from BL was calculated as the Day 168 value minus the BL value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking history, history of exacerbation strata, geographical region, BL aPWV and interaction terms of BL by visit and treatment by visit.
Time frame: BL to Day 168
Population: ITT Population: all randomized par. who received at least one dose of study medication. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 24-week Treatment Period (Day 168) | -1.97 meters per second (m/sec) | Standard Error 0.279 |
| VI 25 µg QD | Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 24-week Treatment Period (Day 168) | -1.95 meters per second (m/sec) | Standard Error 0.241 |
| FF/VI 100/25 µg QD | Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 24-week Treatment Period (Day 168) | -1.75 meters per second (m/sec) | Standard Error 0.256 |
p-value: 0.96995% CI: [-0.71, 0.74]Mixed Models Analysis
p-value: 0.56895% CI: [-0.53, 0.96]Mixed Models Analysis
p-value: 0.56695% CI: [-0.49, 0.89]Mixed Models Analysis
Secondary
Change From BL in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 168
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry at Screening, Days 1, 28, 84, 126, and 168. BL FEV1 was defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 was defined as the mean of the FEV1 values obtained 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was preformed using a repeated measures model with covariates of visit, treatment, history of exacerbation strata, geographical region, BL FEV1 and interaction terms of BL by visit and treatment by visit.
Time frame: BL to Day 168
Population: ITT Population. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Change From BL in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 168 | -0.049 Liters (L) | Standard Error 0.0221 |
| VI 25 µg QD | Change From BL in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 168 | 0.033 Liters (L) | Standard Error 0.0202 |
| FF/VI 100/25 µg QD | Change From BL in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 168 | 0.106 Liters (L) | Standard Error 0.021 |
p-value: 0.00795% CI: [0.023, 0.141]Mixed Models Analysis
p-value: <0.00195% CI: [0.095, 0.215]Mixed Models Analysis
p-value: 0.01295% CI: [0.016, 0.131]Mixed Models Analysis
Secondary
Mean Number of Occasions Rescue Medication [Albuterol (Salbutamol)] Used During a 24-hour Period Averaged Over the Entire 24-week Treatment Period
Participants were given daily record cards for daily completion from BL (Week -1) through Week 24 (Visit 6) each morning and prior to taking study medication (i.e., single-blind and double-blind study medication) supplemental medication (albuterol \[salbutamol\] if received) and ipratropium bromide (if received). Participants recorded number of occasions supplemental albuterol/salbutamol (MDI and/or nebules) used over the previous 24 hours and any medical problems that they had experienced and any medication used to treat these medical problems over the previous 24 hours. Analysis was performed using an analysis of covarience (ANCOVA) model with covariates of treatment, BL mean of occasions of rescue medication use (Week -1), history of exacerbation, and geographical region.
Time frame: BL (Week -1), Week 1 to Week 24
Population: ITT Population: all randomized participants who received at least one dose of study medication. Only those participants with at least 1 on treatment rescue medication measurement during the treatment period and without missing covariate information were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo QD | Mean Number of Occasions Rescue Medication [Albuterol (Salbutamol)] Used During a 24-hour Period Averaged Over the Entire 24-week Treatment Period | 1.97 Occasions per 24 hours | Standard Error 0.093 |
| VI 25 µg QD | Mean Number of Occasions Rescue Medication [Albuterol (Salbutamol)] Used During a 24-hour Period Averaged Over the Entire 24-week Treatment Period | 1.50 Occasions per 24 hours | Standard Error 0.089 |
| FF/VI 100/25 µg QD | Mean Number of Occasions Rescue Medication [Albuterol (Salbutamol)] Used During a 24-hour Period Averaged Over the Entire 24-week Treatment Period | 1.47 Occasions per 24 hours | Standard Error 0.095 |
p-value: <0.00195% CI: [-0.72, -0.22]ANCOVA
p-value: <0.00195% CI: [-0.76, -0.24]ANCOVA
p-value: 0.80395% CI: [-0.29, 0.22]ANCOVA