Mepolizumab in Chronic Obstructive Pulmonary Diseases (COPD) With Eosinophilic Bronchitis
Some patients with chronic obstructive pulmonary diseases (COPD) have large number of specific white blood cells called eosinophils in their airways. These cells are also responsible for causing episodes of worsened respiratory symptoms (exacerbations) and often cause irreversible damage to the airways . This subset of COPD patients often require oral steroids to bring down the number of eosinophils in their airways. Steroids have harmful effects on several of our body systems like bones, blood pressure, blood glucose control and can cause recurrent infections. Mepolizumab is a drug that specifically targets eosinophils reducing the number in the airway. This drug has been shown to be effective in decreasing exacerbation rates and time to exacerbation in asthma patients with eosinophils in their airways. Targeting eosinophils in COPD patients has been shown to reduce severe exacerbations. Hence it is likely that COPD patients with eosinophils in their airways will benefit similarly and have reduced rates and time to exacerbation.
Study Hypothesis:Does mepolizumab decrease sputum eosinophils in patients with fixed airflow obstruction (COPD) and eosinophilic bronchitis?
Chronic Obstructive Pulmonary Diseases
Chronic Airways Limitation
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Mepolizumab in COPD With Eosinophilic Bronchitis: A Randomized Clinical Trial|
- Percentage decrease of sputum eosinophils from baseline [ Time Frame: 6 months ] [ Designated as safety issue: No ]The results will be expressed as absolute changes in percent counts and as fold changes
- Proportion of patients with a major exacerbation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
|Study Start Date:||January 2012|
|Estimated Study Completion Date:||March 2015|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
|Active Comparator: mepolizumab||
This is an anti IL-5 which is given once a month intravenously at the dose of 750 mg.Before use, each vial of mepolizumab will be reconstituted with 5.0 mL of sterile water for injection and swirled gently to enable complete dissolution of the product. This typically takes about 5 minutes. The reconstituted solution contains approximately 50 mg/mL (i.e., a total of 250 mg) of mepolizumab. Three vials of mepolizumab (each reconstituted in 5 mL of sterile water for injection) are needed for a 750 mg dose. The total volume of 15 mL, will be diluted in a 100 mL bag of normal saline solution (0.9%, 154 mmol/L sodium chloride) from which 15 mL of saline has previously been removed.
Other Name: SB-240563
|Placebo Comparator: placebo||
The placebo will consist of 100 mL normal saline solution (0.9%, 154 mmol/L sodium chloride).
Other Name: Normal saline
The current standard of care of patients with moderate to severe COPD is a combination of inhaled corticosteroids, long-acting beta agonist and a long-acting muscarinic agonist (3-5). This treatment recommendation does not consider the heterogeneity of bronchitis in patients with COPD. A third of patients with COPD without asthma may have an eosinophilic bronchitis that is likely to respond to inhaled corticosteroids or prednisone. Approximately 1 in 5 exacerbations are also likely to be associated with an eosinophilic exacerbation (6). This is unlikely to be controlled or prevented by the current recommendations that do not examine bronchitis at the time of exacerbations. None of the major clinical trials that have evaluated treatments that form the basis of current guidelines have examined bronchitis at the time of exacerbations.
Quantitative cell counts in sputum provide a reliable method to assess bronchitis. Sputum can be safely induced with hypertonic saline even in patients with moderate and severe COPD. Similarly to asthma (7), the presence of eosinophils in sputum is a predictor of short-term response in FEV1 and quality of life to inhaled (8) and oral corticosteroids (9). A single study has demonstrated that normalizing eosinophils in sputum in patients with COPD reduces severe exacerbations and hospitalizations by approximately 60% (10). The relative risk reduction in this study is greater than that demonstrated by any study conducted so far in COPD. Long-term studies have not been conducted.
Our recent experience with mepolizumab demonstrated that specifically targeting eosinophils in patient with severe asthma had a prednisone-sparing effect (11) and decrease exacerbations (11,12). In this study it also improved their lung function including in those patients with associated COPD. This is not surprising given that persistent airway eosinophilia can contribute to airway remodeling (13). Indeed, the improvement in FEV1 was associated with a decrease in sputum hyaluron (14) over the six month treatment period. Changes in lung function and symptoms have not been consistently observed in previous mepolizumab trials (12,15). This is clearly related to how precise the patients where phenotyped in terms of sputum eosinophilia. In studies that recruited patients who had persistent sputum eosinophilia, decrease in exacerbations were associated with improvements in FEV1 (16).
It is thus likely that a specific treatment such as anti-IL5 directed against eosinophils would be superior to the current standard treatment in decreasing exacerbations in patients with COPD who continue to have eosinophils in their airway and whose airway disease has an eosinophil-driven component as evidenced by persistent airway eosinophilia.
|Contact: Parameswaran Nair, MD,PhD,FRCP||905-522-1155 ext email@example.com|
|Firestone Institute of Respiratory Health, St Joseph's Hospital||Recruiting|
|Hamilton, Ontario, Canada, L8N 4A6|
|Contact: Melanie Kjarsgaard, BSc., RRT 905-522-1155 ext 33024 firstname.lastname@example.org|
|Principal Investigator: Parameswaran Nair, MD,PhD,FRCP|
|Principal Investigator:||Parameswaran Nair, MD,PhD,FRCP||Associate Professor of Medicine,Division of Respirology, McMaster University|