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Mepolizumab in Chronic Obstructive Pulmonary Diseases (COPD) With Eosinophilic Bronchitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01463644
Recruitment Status : Completed
First Posted : November 2, 2011
Last Update Posted : September 23, 2015
Sponsor:
Information provided by (Responsible Party):
McMaster University

Tracking Information
First Submitted Date  ICMJE October 28, 2011
First Posted Date  ICMJE November 2, 2011
Last Update Posted Date September 23, 2015
Study Start Date  ICMJE January 2012
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2012)
Percentage decrease of sputum eosinophils from baseline [ Time Frame: 6 months ]
The results will be expressed as absolute changes in percent counts and as fold changes
Original Primary Outcome Measures  ICMJE
 (submitted: November 1, 2011)
Percentage decrease of sputum eosinophils from baseline [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2011)
Proportion of patients with a major exacerbation [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mepolizumab in Chronic Obstructive Pulmonary Diseases (COPD) With Eosinophilic Bronchitis
Official Title  ICMJE Mepolizumab in COPD With Eosinophilic Bronchitis: A Randomized Clinical Trial
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Obstructive Pulmonary Diseases
  • Chronic Airways Limitation
  • Bronchitis
Intervention  ICMJE
  • Drug: Mepolizumab
    This is an anti IL-5 which is given once a month intravenously at the dose of 750 mg.
    Other Name: SB-240563
  • Drug: placebo
    The placebo will consist of 100 mL normal saline solution (0.9%, 154 mmol/L sodium chloride).
    Other Name: Normal saline
Study Arms  ICMJE
  • Active Comparator: mepolizumab
    Intervention: Drug: Mepolizumab
  • Placebo Comparator: placebo
    Intervention: Drug: placebo
Publications * Dasgupta A, Kjarsgaard M, Capaldi D, Radford K, Aleman F, Boylan C, Altman LC, Wight TN, Parraga G, O'Byrne PM, Nair P. A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis. Eur Respir J. 2017 Mar 15;49(3). pii: 1602486. doi: 10.1183/13993003.02486-2016. Print 2017 Mar.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 21, 2015)
19
Original Estimated Enrollment  ICMJE
 (submitted: November 1, 2011)
40
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences
  • Sputum eosinophils > 3% at randomization and on at least one occasion in the past 2 years. If this historic data is not available, documented improvement in FEV1 of at least 12% with a course of prednisone in the past 2 years will be used as a surrogate for the presence of airway eosinophilia
  • FEV1/Vital Capacity (VC) < 70% and FEV1 < 60% of predicted normal values calculated using NHANES III reference equations at Screening Visit
  • At least one major exacerbation requiring prednisone in the preceding 12 months. If patients are currently well controlled by optimizing their sputum cell counts (eosinophils < 2%), they should have documented history of exacerbations when their eosinophilia was uncontrolled.
  • A signed and dated written informed consent prior to study participation.
  • Smoking History: Current or former cigarette smokers with a history of cigarette smoking of greater than 10 pack-years [number of pack years = (number of cigarettes per day/20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Screening Visit
  • Male or female adults. A female is eligible to enter and participate in the study if she is either of Non-child bearing potential or is of child bearing age and has a negative pregnancy test at screening, and agrees to acceptable contraceptive methods used consistently and correctly

Exclusion Criteria:

  • Current asthma (12% reversibility to a bronchodilator)
  • Sputum eosinophils < 3% on fluticasone (or equivalent) of 250µg bid.
  • Inability to use salmeterol or tiotropium
  • Significant co-morbidity that prevents from participating in the study
  • Known bronchiectasis or immune deficiency disorders that would predispose the patients to recurrent infections.
  • Pregnancy or intent to become pregnant and lactating females
  • Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Screening Visit
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01463644
Other Study ID Numbers  ICMJE RP11-3588
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party McMaster University
Study Sponsor  ICMJE McMaster University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Parameswaran Nair, MD,PhD,FRCP Associate Professor of Medicine,Division of Respirology, McMaster University
PRS Account McMaster University
Verification Date September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP