Bronchitis, Chronic Airways Limitation, Chronic Obstructive Pulmonary Diseases
Conditions
Keywords
Mepolizumab, COPD, eosinophilic bronchitis, exacerbation, anti-interleukin 5 (IL5)
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
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 sputum eosinophil counts and exacerbations and decrease structural changes (remodelling) 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.
Interventions
DRUGMepolizumab
This is an anti IL-5 which is given once a month intravenously at the dose of 750 mg.
DRUGplacebo
The placebo will consist of 100 mL normal saline solution (0.9%, 154 mmol/L sodium chloride).
Sponsors
McMaster University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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 Forced expired volume in 1 second (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Decrease of Sputum Eosinophils From Baseline to End of Therapy (6 Months) | 6 months | The results will be expressed as absolute changes in percent sputum eosinophil counts from baseline to end of therapy (at 6 months). Change is difference in sputum eosinophils between baseline/time zero to end of therapy/6 months. A larger number represents a greater degree in the reduction of sputum eosinophils. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With a Major Exacerbation. | Baseline to 6 months | Exacerbation: a sustained worsening of the patient's respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD Major exacerbation will be defined as a symptomatic deterioration requiring treatment with antibiotics, oral or intravenous corticosteroids, hospitalization, or a combination of these. |
Countries
Canada
Participant flow
Recruitment details
Patients who met eligibility criteria after the screening visit entered a 24 week double-blind treatment period followed by one follow-up visit.
Pre-assignment details
Eligible adult patients were enrolled by baseline post-bronchodilator FEV1/VC\<70% and post bronchodilator FEV1 \<60% predicted), greater than 10 pack years and sputum eosinophils greater than/equal to 3%. Patients were then randomized to either mepolizumab 750 mg every 4 weeks (Q4W) or matched placebo in a 1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Mepolizumab Mepolizumab: This is an anti interleukin-5 (IL-5) which is given once a month intravenously at the dose of 750 mg. | 8 |
| Placebo placebo: The placebo consisted of 100 mL normal saline solution (0.9%, 154 mmol/L sodium chloride). | 10 |
| Total | 18 |
Baseline characteristics
| Characteristic | Total | Placebo | Mepolizumab |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 5.97 | 67 years STANDARD_DEVIATION 5.89 | 65 years STANDARD_DEVIATION 6.31 |
| Blood eosinophil count | 0.5 cells/mm^3 STANDARD_DEVIATION 0.42 | 0.33 cells/mm^3 STANDARD_DEVIATION 0.29 | 0.69 cells/mm^3 STANDARD_DEVIATION 0.5 |
| Chronic Respiratory Questionnaire (CRQ) scores | 87.60 units on a scale STANDARD_DEVIATION 20.34 | 82.7 units on a scale STANDARD_DEVIATION 21.16 | 93.75 units on a scale STANDARD_DEVIATION 18.75 |
| COPD Assessment test (CAT) scores | 23 units on a scale | 25 units on a scale | 16 units on a scale |
| Diffusion capacity (DLCO) | 14.60 ml CO/min/mmHg STANDARD_DEVIATION 4.47 | 14.39 ml CO/min/mmHg STANDARD_DEVIATION 4.54 | 14.92 ml CO/min/mmHg STANDARD_DEVIATION 4.67 |
| Post bronchodilator FEV1 | 1.40 litres STANDARD_DEVIATION 0.54 | 1.24 litres STANDARD_DEVIATION 0.52 | 1.53 litres STANDARD_DEVIATION 0.57 |
| Postbronchodilator FEV1% | 45.00 percentage | 35.00 percentage | 58.50 percentage |
| Post bronchodilator FEV1/SVC | 44.00 percentage | 37.21 percentage | 55.11 percentage |
| Post bronchodilator SVC | 3.00 litres STANDARD_DEVIATION 0.75 | 3.09 litres STANDARD_DEVIATION 0.76 | 2.79 litres STANDARD_DEVIATION 0.74 |
| Pre bronchodilator FEV1% | 34.00 percentage | 29.50 percentage | 55.00 percentage |
| Pre bronchodilator forced expiratory volume in 1 second (FEV1) | 1.10 forced expiratory volume in litres STANDARD_DEVIATION 0.42 | 0.99 forced expiratory volume in litres STANDARD_DEVIATION 0.28 | 1.35 forced expiratory volume in litres STANDARD_DEVIATION 0.49 |
| Pre bronchodilator slow vital capacity (SVC) | 2.80 litres STANDARD_DEVIATION 0.56 | 2.85 litres STANDARD_DEVIATION 0.46 | 2.69 litres STANDARD_DEVIATION 0.68 |
| Proportion of Patients With a Major Exacerbation | 11 Participants | 7 Participants | 4 Participants |
| Residual Volume (RV) | 2.90 litres STANDARD_DEVIATION 0.84 | 3.39 litres STANDARD_DEVIATION 0.77 | 2.36 litres STANDARD_DEVIATION 0.56 |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 13 Participants | 9 Participants | 4 Participants |
| Sputum eosinophil count (%) | 10.10 percentage of eosinophils | 7.35 percentage of eosinophils | 11 percentage of eosinophils |
| Sputum hyaluronan | 517 ng/ml | 517 ng/ml | 466 ng/ml |
| Sputum neutrophil count (%) | 63.6 percentage STANDARD_DEVIATION 17.22 | 70.9 percentage STANDARD_DEVIATION 15.7 | 54.5 percentage STANDARD_DEVIATION 15.2 |
| Sputum versican | 3.57 ng/ml | 3.55 ng/ml | 3.74 ng/ml |
| Total cell count/g of sputum | 8.20 cells per gram of sputum | 11.6 cells per gram of sputum | 4.10 cells per gram of sputum |
| Total Lung Capacity (TLC) | 5.90 litres STANDARD_DEVIATION 1.16 | 6.60 litres STANDARD_DEVIATION 1.01 | 5.20 litres STANDARD_DEVIATION 0.85 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 10 |
| other Total, other adverse events | 4 / 8 | 4 / 10 |
| serious Total, serious adverse events | 2 / 8 | 1 / 10 |
Outcome results
Primary
Percentage Decrease of Sputum Eosinophils From Baseline to End of Therapy (6 Months)
The results will be expressed as absolute changes in percent sputum eosinophil counts from baseline to end of therapy (at 6 months). Change is difference in sputum eosinophils between baseline/time zero to end of therapy/6 months. A larger number represents a greater degree in the reduction of sputum eosinophils.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mepolizumab | Percentage Decrease of Sputum Eosinophils From Baseline to End of Therapy (6 Months) | 11.28 percentage | Standard Deviation 6.6 |
| Placebo | Percentage Decrease of Sputum Eosinophils From Baseline to End of Therapy (6 Months) | 7.07 percentage | Standard Deviation 11.49 |
Secondary
Proportion of Patients With a Major Exacerbation.
Exacerbation: a sustained worsening of the patient's respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD Major exacerbation will be defined as a symptomatic deterioration requiring treatment with antibiotics, oral or intravenous corticosteroids, hospitalization, or a combination of these.
Time frame: Baseline to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mepolizumab | Proportion of Patients With a Major Exacerbation. | 4 participants |
| Placebo | Proportion of Patients With a Major Exacerbation. | 7 participants |