A 24-week Arterial Stiffness Study With Fluticasone Furoate/Vilanterol in COPD

Study Overview
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Brief Summary
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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.

Official Title
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A 24-week Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol 100/25 mcg Inhalation Powder Delivered Once-daily Via a Novel Dry Powder Inhaler on Arterial Stiffness Compared With Placebo and Vilanterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD).

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Fluticasone Furoate/Vilanterol
* Drug: Vilanterol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluticasone Furoate/Vilanterol<br>Inhaled corticosteroid/long acting beta-agonist | Drug: Fluticasone Furoate/Vilanterol<br>* Inhaled corticosteroid/long acting beta-agonist<br>|
| Experimental: vilanterol<br>Inhaled long acting beta-agonist | Drug: Vilanterol<br>* Inhaled long acting beta-agonist<br>|
| Placebo Comparator: placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | BL to Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | BL to Day 168 | 
| 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. | BL (Week -1), Week 1 to Week 24 |