Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
This study is designed to evaluate the effect of fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) Inhalation Powder once daily (QD) on arterial stiffness compared with Tiotropium QD over 12 week treatment period in subjects with COPD and aortic pulse wave velocity (aPWV) \> 12.0 m/s at Visit 1. Arterial stiffness will be measured as aPWV. This is a comparator, randomised, double-blind, double-dummy, parallel group, multi-centre study. Subjects who meet the eligibility criteria at Screening and meet the randomization criteria at the end of a 2-week Run-In period will enter a 12-week treatment period. There will be an approximate 7-day Follow-up period after the treatment period.
Detailed description
This is a Phase IIIb comparator, double-blind, double-dummy, randomised (1:1), parallel group, multi-centre study. At Visit 1 (Screening Visit), subjects who meet the pre-defined Inclusion Criteria and none of the Exclusion Criteria will enter a 2-week, single-blind placebo Run-in Period. The purpose of the Run-In Period is to monitor albuterol/salbutamol use at baseline, and to ensure that subjects' COPD is at a stable stage at randomization. Subject's adherence with study procedures, diary completion will also be evaluated during the Run-In Period. At the end of the Run-in period, subjects will be assessed and those who meet the randomisation criteria will receive one of the following two double-blind treatments for 12 weeks: * FF (100 mcg)/VI (25 mcg) administered QD via a NDPI in the morning * Tiotropium (18 mcg) administered QD via a HandiHaler in the morning To ensure blinding of the treatments and to ensure a double-dummy design matching NDPI and HandiHaler will be utilised. Each subject will be instructed to self administer blinded study drug during the double blind treatment period as follows: * Each morning take 1 inhalation from NDPI containing FF (100 mcg)/VI (25 mcg) followed by 1 inhalation from placebo capsule delivered via HandiHaler. * Each morning take 1 inhalation from matching placebo NDPI followed by 1 inhalation from a capsule containing tiotropium 18 mcg delivered via HandiHaler. An inhaled short acting beta2-receptor agonist, salbutamol/albuterol will be provided to subjects to use as needed throughout the Run-in and Treatment periods for relief of COPD symptoms. Ipratropium bromide is permitted if the subject is on a stable dose from Screening (Visit 1) and remains on the stable dose throughout the study. Subjects who experience an exacerbation of their COPD (which requires medication in addition to an increase in rescue medication) or a lower respiratory tract infection (LRTI) during the run-in period are not eligible to enter the treatment period. Any subject who experiences a similar COPD exacerbation (sec 4.4) or LRTI at any time on therapy will be withdrawn from the study. The aPWV will be measured at Screening and clinic Visits 3-5. Disease specific health status will be evaluated using the St. George's Respiratory Questionnaire (SGRQ-C), Euro Qol Questionnaire (EQ-5D) for COPD patients and the COPD Assessment Test (CAT) at Visit 2 (Day 1) and at Visit 5 (Weeks 12). The 12-lead ECG will be evaluated at Visit 1 (Screening) only. Vital signs (blood pressure and pulse rate), spirometry measurements, and clinical laboratory tests (hematology and chemistry) and other study-specific safety assessments will be obtained at selected clinic visits. A follow-up phone call will occur approximately 7 days after the last clinic visit. The overall study duration from Screening to Follow-up for each subject is approximately 15 weeks. Subjects will be considered to have completed the study upon completion of assessments and procedures up to and including completion of Follow-up Phone Contact (7 ± 2 days post Visit 5).
Interventions
DRUGfluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI)
fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder delivered once daily via a Novel Dry Powder Inhaler (NDPI)
DRUGTiotropium
• Tiotropium (18 mcg) administered QD via a HandiHaler
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type of subject: Outpatient * Informed consent: Subjects must give their signed and dated written informed consent to participate. * Gender: Male or female subjects. * Age: greater then or equal to 40 years of age at Screening (Visit 1) * COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society (ATS) /European Respiratory Society(ERS). * Subjects with a current or prior history ofgreater then or equal to 10 pack-years of cigarette smoking at Screening (Visit 1). * Subjects with a measured post-albuterol/salbutamol FEV1 less then 70% of predicted at Screening (Visit 1). * Subjects with a measured post-albuterol/salbutamol FEV1/FVC ratio of less then or equal to 0.70 at Screening (Visit 1). * Exacerbation History: Subjects who have been hospitalised or have been treated with oral corticosteroids or antibiotics for their COPD within the last 3 years prior to Screening (V1). * Baseline aPWV: subjects with a measured aPWV greater then 12.0 m/s at Screening (Visit 1).
Exclusion criteria
* Body Mass Index of less then or equal to 35
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84) | Baseline to Day 84 (Early Withdrawal) | 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/2pR, 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 p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit. |
Countries
Argentina, France, Germany, Italy, Norway, Russia, Ukraine
Participant flow
Recruitment details
A total of 260 participants were randomized. Three of these participants were randomized in error (they were determined not to have met entry criteria and were classified as run-in/screen failures); thus, they did not receive investigational product and are not captured in the Treatment Period table of the Participant Flow module.
Pre-assignment details
At Visit (V) 1, eligible participants (par.) entered a 2-week, single-blind placebo Run-in Period (RIP) to establish a stable baseline. At V 2, eligible par. were randomized to a 12-week, double-blind, double-dummy Treatment Period. 802 par. were screened, 279 par. entered the RIP, and 257 par. were randomized and received \>=1 study treatment dose.
Participants by arm
| Arm | Count |
|---|---|
| FF/VI 100/25 µg Participants self-administered one inhalation of Fluticasone Furoate /Vilanterol (FF/VI) 100/25 micrograms (µg) via a dry powder inhaler (DPI) followed by 2 inhalations from a single placebo capsule delivered via a HandiHaler in the morning for 12 weeks. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of Chronic Obstructive Pulmonary Disease (COPD) symptoms. | 127 |
| Tiotropium Bromide 18 µg Participants self-administered one inhalation of placebo via an DPI followed by 2 inhalations from a single capsule containing Tiotropiuum Bromide 18 µg via a HandiHaler. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of COPD symptoms. | 130 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 2-week Run-in Period | Adverse Event | 2 | 0 | 0 |
| 2-week Run-in Period | Continuation Criteria Not Met | 13 | 0 | 0 |
| 2-week Run-in Period | Lost to Follow-up | 1 | 0 | 0 |
| 2-week Run-in Period | Protocol Violation | 2 | 0 | 0 |
| 2-week Run-in Period | Withdrawal by Subject | 4 | 0 | 0 |
| Treatment Period (TP) | Adverse Event | 0 | 7 | 6 |
| Treatment Period (TP) | Lack of Efficacy | 0 | 4 | 3 |
| Treatment Period (TP) | Met Protocol-defined Stopping Criteria | 0 | 1 | 0 |
| Treatment Period (TP) | Protocol Violation | 0 | 1 | 5 |
| Treatment Period (TP) | Withdrawal by Subject | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | FF/VI 100/25 µg | Tiotropium Bromide 18 µg | Total |
|---|---|---|---|
| Age, Continuous | 66.7 Years STANDARD_DEVIATION 7.2 | 67.7 Years STANDARD_DEVIATION 7.34 | 67.3 Years STANDARD_DEVIATION 7.28 |
| Race/Ethnicity, Customized White - White/Caucasian/European | 127 participants | 130 participants | 257 participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 108 Participants | 112 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 127 | 8 / 130 |
| serious Total, serious adverse events | 7 / 127 | 8 / 130 |
Outcome results
Primary
Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84)
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/2pR, 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 p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit.
Time frame: Baseline to Day 84 (Early Withdrawal)
Population: Intent-to-Treat (ITT) Population: all participants (par.) who were randomized to and received \>=1 dose of randomized medication in the TP. The analysis model included all par. in the ITT Population without missing covariate information (MCI) and with \>=1 post-BL measurement. Par. presented represent those with data available at Day 84 without MCI.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF/VI 100/25 µg | Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84) | -0.859 meters per second (m/sec) | Standard Error 0.259 |
| Tiotropium Bromide 18 µg | Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84) | -1.118 meters per second (m/sec) | Standard Error 0.262 |
p-value: 0.48495% CI: [-0.468, 0.986]Mixed Models Analysis