Mepolizumab Effectiveness in Severe Eosinophilic Asthma and Bronchiectasis

Study Overview
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Brief Summary
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Asthma is a chronic respiratory disorder characterized by bronchial inflammation and reversible bronchial obstruction. Severe asthma is an extremely heterogeneous disease, often associated with several comorbidities and risk factors. Severe uncontrolled asthma associated with bronchiectasis is an emerging phenotype. Several studies have attempted to establish an association between asthma and bronchiectasis. Mepolizumab, an Interleukin-5 (IL-5) antagonist, reduces exacerbations, eosinophils, and improves pulmonary function and asthma control. IL-5 is pivotal to eosinophils maturation and release from bone marrow, their subsequent accumulation, activation and persistence in the tissues. IL-5 therefore represents an attractive target to prevent or blunt eosinophils-mediated inflammation. The investigators hypothesize that eosinophils, stimulated by IL-5, play a crucial role in severe asthma and BE pathogenesis.

Detailed Description
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Asthma is a chronic respiratory disorder in which bronchial inflammation, airway hyperresponsiveness, and reversible bronchial obstruction are operant, inciting daily symptoms and triggering unpredictable acute exacerbations. The prevalence of severe asthma varies between 5 and 10% of asthma frameworks and is estimated to account for >60% of the total costs of the disease. Severe asthma warrants Global Initiative for Asthma (GINA) Step 4 or 5 treatment, (e.g. high-dose Inhaled Corticosteroids/Long Acting Beta2-Agonists (ICS/LABA), to achieve control or remains 'uncontrolled' (entirely or in part) despite this or other appropriate therapeutic intervention. Severe asthma is an extremely heterogeneous disease, often associated with several comorbidities and risk factors, leading to divide accordingly severe asthmatic patients into homogenous groups. The result is the identification of several phenotypes of severe asthma, as those associated with obesity, smoking habit, chronic obstructive pulmonary disease (COPD), gastro-oesophageal reflux disease (GERD), chronic rhinosinusitis, nasal polyposis, infections and others. In recent years, the recognition and treatment of comorbidities is crucial because can potentially improve asthma control and outcomes. Severe uncontrolled asthma associated with bronchiectasis is an emerging phenotype. Several studies have attempted to establish an association between asthma and bronchiectasis. The prevalence of bronchiectasis (BE) is significantly higher in severe asthma (range 24-40%), then in milder disease (3%). At least one third of patients with severe asthma show the presence of BE on high resolution chest computed tomography (HRCT) scan. This phenotype has been described particularly in patients with severe, late-onset eosinophilic asthma. In order to improve the therapeutic approach to the more severe forms of asthma, biological treatments have been realized. Recently, mepolizumab, an IL-5 antagonist, was commercialized. Mepolizumab reduces exacerbations, eosinophils, and improves pulmonary function and asthma control. There is a considerable evidence that implicates eosinophils as important effector cells in the eosinophilic asthma inflammation. IL-5 is pivotal to eosinophils maturation and release from bone marrow, their subsequent accumulation, activation and persistence in the tissues. IL-5 therefore represents an attractive target to prevent or blunt eosinophils-mediated inflammation. The investigators hypothesize that eosinophils, stimulated by IL-5, play a crucial role in severe asthma and BE pathogenesis. Accumulation of eosinophils at the bronchial level causes damage by degranulation and release of toxic protein, mucus hypersecretion, elastolytic activity, mucinous cells hypertrophy and oxidative stress. Airway remodeling, due to the activity of eosinophils, is the consequence of ongoing inflammation and repair. All these tissue changes are characteristic of both asthma and bronchiectasis (BE). BE, in effect, is caused by long-term excessive inflammatory damage to the airways and in patients with asthma, eosinophils may further contribute to tissue injury. The investigators therefore hypothesize that treatment with mepolizumab, targeted against IL-5 activity, in patients with severe eosinophilic asthma associated with bronchiectasis may lead to a reduction of bronchiectasis and asthma exacerbations and lead to improve control of asthma.

Official Title
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Mepolizumab Effectiveness in Patients With Severe Eosinophilic Asthma and Co-presence of Bronchiectasis

Conditions
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Bronchial Asthma, Bronchiectasis

Intervention / Treatment
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* Biological: Mepolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female with age greater than or equal to 18 years; Severe eosinophilic asthma diagnosis according to GINA 2019 report Evidence of bronchiectasis in at least one lung lobe in the chest CT scan performed prior to mepolizumab treatment; Presence of daily expectoration; At least 3 bronchiectasis exacerbations in the year prior to mepolizumab treatment, documented through medical documentation, which required treatment with antibiotics; Informed consent obtained from the patient. Exclusion Criteria: Poor adherence to severe asthma therapy Patients with other respiratory disease that may share common clinical manifestations of severe asthma (i.e. acute bronchopulmonary aspergillosis, vasculitis and COPD) Any medical condition or disease that was not stable during the 3 months prior to mepolizumab treatment (excluding asthma exacerbations), that the investigator believes may compromise the safety of the patient if enrolled in the study such us atrial fibrillation, acute respiratory failure, acute heart failure, myocardial infarction and acute renal failure. Bronchiectasis associated with cystic fibrosis; Traction bronchiectasis in the context of pulmonary fibrosis; History of lung cancer in the previous 5 years; History of significant hemoptysis (≥300 mL of blood) or which required embolization or blood transfusions within 6 weeks prior to mepolizumab treatment; Use of drugs that can influence the response to treatment such us immunosuppressant and/or biological therapies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Severe Asthma+BE<br>Patients with severe eosinophilic asthma with co-presence of Bronchiectasis (BE) in treatment with Mepolizumab | Biological: Mepolizumab<br>* Subcutaneous Mepolizumab (100 mcg) injection in patients with severe eosinophilic asthma<br>|
| Active Comparator: Severe Asthma without BE<br>Patients with severe eosinophilic asthma without Bronchiectasis (BE) in treatment with Mepolizumab | Biological: Mepolizumab<br>* Subcutaneous Mepolizumab (100 mcg) injection in patients with severe eosinophilic asthma<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of Asthma Control Test (ACT) score at Week 12 (T3), at Week 24 (T6) and at Week 52 (T12). | Asthma Control Test (ACT) score is validated five-points scoring system, self-administered assessing the control of Asthma. Scores range from 5 points (worst asthma control) to 25 points (better asthma control). Change = Week 12 (T3) - Baseline score; Week 24 (T6) - Baseline score; Week 52 (T12) - Baseline score. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline values of Spirometry values (expressed in Litre) at Week 12 (T3), at Week 24 (T6) and at Week 52 (T12). | Spirometry assess the airways obstruction. Spirometry will be performed according to American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. The main benchmarks for assessing airways obstruction are: Forced Expiratory Volume in 1 second (FEV1) and Forced Vital Capacity (FVC), expressed in Litre (L) respectively. Change = Week 12 (T3) - Baseline values; Week 24 (T6) - Baseline values; Week 52 (T12) - Baseline values. | Baseline and Week 52 |