Effect of an Inhaled Glucocorticoid-long-acting Beta Adrenergic Agonist on Endothelial Function in COPD

Study Overview
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Brief Summary
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In the present study, the investigators wish to address the effect of a glucocorticoid/long-acting beta-agonist preparation on endothelial function in COPD patients who do not currently smoke (ex-smokers) by measuring endothelium-dependent (albuterol response) and endothelium-independent (NTG response) vasodilation in the bronchial artery, reflecting endothelium-dependent and endothelium-independent vasodilation (drug-induced increase in Qaw, ΔQaw). With this approach the investigators will test the hypothesis that in stable ICS-naïve COPD patients, endothelium-dependent vasodilation is restored with a glucocorticoid/long-acting beta-agonist preparation, presumably resulting from the glucocorticoid component.

Detailed Description
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To test the premise and to characterize the time dependence of the responses, the investigators propose the following two aims: To determine the effect of a medium dose glucocorticoid/long-acting beta-agonist preparation (250 μg fluticasone plus 50 μg salmeterol) administered for 3 weeks on inhaled albuterol and sub-lingual NTG induced vasodilation in the bronchial artery, as assessed by ΔQaw in stable glucocorticoid-naïve COPD patients, and to re-assess the responses after a 3 week glucocorticoid/long-acting beta-agonist washout period. To determine inhaled albuterol and sub-lingual NTG-induced vasodilation (ΔQaw) before, and 30 min and 120 min after a single medium dose of an ICS (220 μg fluticasone) in stable glucocorticoid- naïve COPD patients. For both aims, the protocol design will be placebo-controlled and double-blind. For the second aim, only fluticasone pretreatment will be possible because the salmeterol component of the fluticasone/salmeterol combination preparation could influence albuterol responsiveness irrespective of any glucocorticoid effect. The timing of the endothelial function measurements in the long-term glucocorticoid/long-acting beta-agonist protocol and single dose ICS protocol is based on the past experience with ICS on airway vascular function. Single dose effects were seen within 15-30 min and waned by 90 min (25,26), while long-term treatment effects were no longer seen 3 weeks after ICS withdrawal (16).

Official Title
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Effect of an Inhaled Glucocorticoid-long-acting Beta Adrenergic Agonist on Endothelial Function in COPD

Conditions
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COPD

Intervention / Treatment
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* Drug: Placebo
* Drug: Fluticasone /salmeterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Smoking history of at least 10 pack-years and to have quit smoking at least 1 year before the study. -Diagnosis of COPD Post-bronchodilator FEV1 of less than 75% of predicted and FEV1/FVC ratio less than 0.7 (GOLD stage ≥2). At entry into the study, the subjects will have to be clinically stable; they will be allowed to use short-acting and long-acting β2 - adrenergic agonists and cholinergic antagonists as their usual airway medication. Exclusion Criteria: Women of childbearing potential who do not use accepted birth control measures; pregnant and breast feeding women. Use of cardiovascular medications that cannot be held on the study days Use of oral airway medications or anti-inflammatory agents Subjects with known beta-adrenergic agonist or NTG intolerance Acute respiratory infection within four weeks prior to the study A body mass index > 30

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Matching Placebo<br>Participants will be treated with placebo twice a day for 3 weeks. | Drug: Placebo<br>* participants will be assigned to 3-weeks treatment of inhaled placebo twice a day<br>Drug: Fluticasone /salmeterol<br>* Participant will be assigned to a 3-weeks treatment with inhaled fluticasone/salmeterol or matching placebo<br>* Other names: Advair 250/50;|
| Active Comparator: Fluticasone/salmeterol<br>Participants will be assigned to inhaled fluticasone/salmeterol twice a day for 3 weeks. | Drug: Fluticasone /salmeterol<br>* Participant will be assigned to a 3-weeks treatment with inhaled fluticasone/salmeterol or matching placebo<br>* Other names: Advair 250/50;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| long term effect of a glucocorticoid/long-acting beta-agonist on endothelial function in the bronchial artery. | To determine the effect of a medium dose glucocorticoid/long-acting beta-agonist preparation (250 μg fluticasone plus 50 μg salmeterol) or placebo administered for 3 weeks on inhaled albuterol and sub-lingual NTG induced vasodilation in the bronchial artery, as assessed by ΔQaw in stable glucocorticoid-naïve COPD patients, and to re-assess the responses after a 3 week washout period. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| acute effect of an ICS on bronchial endothelial function in stable glucocorticoid-naïve COPD patient. | To determine inhaled albuterol and sub-lingual NTG-induced vasodilation (ΔQaw) before, and 30 min and 120 minutes after a single medium dose of an ICS (220 μg fluticasone)or placebo in stable glucocorticoid-naïve COPD patients | 30 minutes and 120 minutes after inhaled albuterol and sub-lingual NTG | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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airway blood flow,, COPD,, endothelial dysfunction, inhaled corticosteroids