Mepolizumab in Chronic Obstructive Pulmonary Diseases (COPD) With Eosinophilic Bronchitis
Condition: Chronic Obstructive Pulmonary Diseases; Chronic Airways Limitation; Bronchitis
MeSH terms: Bronchitis; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Acute Disease
Study type: Interventional
Phase: Phase 3

Summary: 
      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?
    

Detailed description: 
      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 forced expiratory volume at one second (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.
    

Intervention name(s): Mepolizumab; placebo
Intervention type(s): Drug; Drug
Intervention description(s): This is an anti IL-5 which is given once a month intravenously at the dose of 750 mg.; The placebo will consist of 100 mL normal saline solution (0.9%, 154 mmol/L sodium chloride).
Other intervention name(s): SB-240563; Normal saline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Mepolizumab; COPD; eosinophilic bronchitis; exacerbation; anti-interleukin 5 (IL5)