Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial
Official title:
Effects of Fluticasone/Salmeterol (Advair®) in Outpatients With Chronic Obstructive Pulmonary Disease (COPD) Acute Exacerbation
Short course of steroids in COPD exacerbation improves FEV1 and decreases the relapse rate. However, some concerns remain about using systemic steroids for all patients with acute exacerbation. Their short-term advantages may be outweighed by the occurrence of adverse side effects such as hyperglycemia, which is difficult to manage on an outpatient basis. In this context, the possibility of treating patients with COPD exacerbation with inhaled steroids having less systemic adverse effects is interesting. The objectives are to compare relapse rate, lung function, the severity of dyspnea and, systemic and sputum inflammatory markers in outpatients with acute COPD exacerbations treated with fluticasone/salmeterol (Advair®) or oral prednisone for 10 days. The hypothesis is that Advair® is as effective as prednisone in treatment of outpatients with COPD exacerbation. The primary endpoint is to determine if the relapse rate at one month is equivalent for both treatments. The secondary endpoints are to compare lung function and dyspnea score and, systemic and sputum inflammatory markers modulation after 10 days of both treatments. We will recruit 30 outpatients in each group from our COPD clinic. Patients will receive prednisone (40mg/day) with placebo diskus or Advair® 50/500ug 2 inhalations bid (twice the regular dose) with placebo pills for 10 days. All patients will receive antibiotics and short-acting bronchodilators as needed. We expect to demonstrate that the improvement of lung function, dyspnea, inflammatory markers and relapse rate are equivalent in both treatments suggesting that Advair® could be a good alternative to prednisone for patients with steroid-induced hyperglycemia.
COPD exacerbations are a common cause of ill health, hospitalization and death. Once
exacerbation symptoms are recognized, the current treatment consists of short course of oral
steroids, antibiotics and increased bronchodilator intake. Systemic steroids are thought to
reduce the inflammatory component of COPD exacerbation. A short course of steroid therapy
improves FEV1 and decreases the relapse rate but most studies have been done on patients
requiring hospitalization. Only few studies have described the role of steroids in the
outpatients setting. However, some concerns remain about using systemic steroids for all
patients with acute exacerbation. Their short-term advantages may be outweighed by the
occurrence of adverse side effects such as hyperglycemia, which is difficult to manage on an
outpatient basis. In this context, the possibility of treating patients with COPD
exacerbation with inhaled steroids having less systemic adverse effects is interesting. In
clinical trials, combination of corticosteroid with long-acting β2-adrenoceptor agonists
(LABA) reduces airway inflammation, exacerbation rates, and improves lung function and
health status of patients with stable moderate to severe COPD beyond that achieved by
individual component therapy. Trials showed that nebulized steroid during acute COPD
exacerbation requiring hospitalization is as effective as prednisone with less
hyperglycemia. To our knowledge, no study has been conducted on the efficacy of combination
treatment with inhaled steroid and LABA in the outpatient management of COPD exacerbation.
Combination treatment could be a good alternative for patients with steroid contraindication
and to reduce hospitalisation for uncontrolled hyperglycemia.
Primary objective: To compare relapse rates, lung function, the severity of dyspnea and,
systemic and sputum inflammatory markers in outpatients with acute exacerbations of COPD
treated with twice the regular dosage of Advair® or oral prednisone for 10 days.
Secondary objectives: To obtain preliminary data allowing sample size calculation for a
larger similar clinical trial.
Hypothesis: Advair® is as effective as oral prednisone in treatment of outpatients with an
acute COPD exacerbation.
Airway inflammation is a component of the pathophysiology of COPD exacerbation. Sputum from
COPD-exacerbation patients has elevated inflammatory cells, TNF, IL-8 and RANTES levels
compared to stable patients. Systemic steroid are thought to reduce the inflammatory
component of COPD exacerbation. Appraisal of the current literature on glucocorticosteroids
for acute COPD exacerbation show that a short course of systemic corticosteroid therapy
improves spirometry and decreases the relapse rate but most studies using steroids for
exacerbation have been done on patients requiring hospitalization, and only few have
described the role of steroids in the outpatients setting. Two randomized controlled trials
studied patients with acute COPD exacerbations not requiring hospitalization. Patients were
assigned to receive oral prednisone for at least 9 days or placebo. The prednisone group
showed a more rapid and significant improvement in forced expiratory volume at one second
(FEV1). This therapy also resulted in fewer treatment failures and a trend toward more rapid
improvement in dyspnea scale scores compared to placebo. However, despite proof of efficacy,
some concerns remain about using systemic corticosteroid for all patients with acute
exacerbation. Mainly because the short-term advantage may be outweighed by the occurrence of
adverse side effects such as hyperglycemia, which is difficult to manage on outpatient basis
and myopathy that can be observed even following a single oral dose of prednisolone. In this
context, the possibility of treating patients with acute COPD exacerbation with inhaled
corticosteroid having less systemic adverse effects is on particular interest.
Two trials have studied the effect of nebulized steroid during acute COPD exacerbation
requiring hospitalization. Maltais et al. showed that 3 days of oral prednisone or nebulized
budesonide significantly increased FEV1 compared to placebo. Compared with prednisone,
nebulized budesonide was associated with a lesser occurrence of hyperglycemia, a potential
advantage for diabetic patients with COPD. Recent studies have suggested long-acting
b2-agonist as potential option in the treatment of acute exacerbation of COPD. It has been
shown that salmeterol (up to 100 mcg) as formoterol (up to 48mcg) given over the same
interval time induced an effective dose-dependent increase in FEV1, FVC and IC in patients
with mild acute COPD exacerbation. Finally, the inhaled combination of
salmeterol/fluticasone during 13 weeks in stable COPD patients showed a significant decrease
in airway inflammation with decrease of lymphocytes, neutrophils, eosinophils and cells
expressing genes for TNF and IFN. The main effect of inhaled corticosteroids is thought to
be mediated through suppression of airway inflammation, while LABA are thought to work by
inducing bronchodilation. However, there is emerging data to indicate that long-acting
b2-adrenoceptor agonists may amplify the anti-inflammatory effects of corticosteroids by
accelerating nuclear translocation of the glucocorticoid receptor complex, and enhancing
transcription and expression of steroid-inducible genes in pro-inflammatory cells. These
results suggest a role of the combination of long-acting b2-adrenoreceptor agonist and
inhaled steroid in the inflammation observed in acute COPD exacerbation.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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