Mepolizumab Treatment for Rhinovirus-induced Asthma Exacerbations

Study Overview
=================
Brief Summary
-----------------
Asthma is a chronic inflammatory disorder of the airways characterized by lower respiratory tract (LRT) symptoms such as wheeze, cough and airway obstruction. Patients with asthma frequently suffer from exacerbations, which can be triggered by allergens and, in particular, viral respiratory infections. It has recently been shown that mepolizumab, a humanized monoclonal antibody that neutralizes interleukin(IL)-5, markedly reduces the exacerbation rate in asthma patients with eosinophilic airway inflammation. Previous studies have indicated that in a mixed population (eosinophilic and non eosinophilic) of mild asthma patients, mepolizumab did not have an impact on lung function and asthma symptom scores upon allergen provocation, although it did on markers such as sputum and blood eosinophils. Together, these observations led to the hypothesis that mepolizumab treatment reduces the exacerbation rate by limiting virus-induced asthma exacerbations. The investigators hypothesize that neutralization of IL-5 during virus infection in patients with allergic asthma: Reduces virus-induced bronchial inflammation Attenuates virus-induced asthma symptoms, airflow limitation and bronchial hyperresponsiveness. Enhances cellular immune responses to the virus. The aims of this study are to: To investigate whether IL-5 neutralization reduces the inflammatory response to viral airway infections in allergic asthma patients To investigate whether IL-5 neutralization prevents or reduces asthma symptoms during virus-induced asthma exacerbations To investigate whether IL-5 neutralization affects the cellular immune response to viral airway infections in allergic asthma patients

Detailed Description
-----------------
Mild allergic asthma subjects receive three times an infusion containing 750 mg of mepolizumab. Two weeks after the third infusion, subjects will be experimentally infected with RV16. One day before and six days after infection a bronchoscopy will be performed to collect bronchoalveolar lavage fluid and bronchial brushes. Blood will be collected at each infusion and each bronchoscopy and at least 6 weeks after infection. Lung function will be evaluated throughout the study.

Official Title
-----------------
The Efficacy of Mepolizumab Treatment on Rhinovirus Induced Asthma Exacerbations

Conditions
-----------------
Asthma, Viral Infection

Intervention / Treatment
-----------------
* Drug: Mepolizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 18 - 50 years History of episodic chest tightness and wheezing Intermittent or mild persistent asthma according to the criteria by the Global Initiative for Asthma Non-smoking or stopped smoking more than 12 months ago and ≤ 5 pack years (PY) Clinically stable, no history of exacerbations within the last 6 weeks prior to the study Steroid-naïve or those patients who are currently not on corticosteroids and have not taken any corticosteroids by any dosing-routes within 2 weeks prior to the study. Occasional usage of inhaled short-acting beta2-agonists as rescue medication is allowed, prior and during the study Baseline FEV1 > 80% of predicted Airway hyperresponsiveness, indicated by a positive acetyl-ß-methylcholine bromide (MeBr) challenge with PC20 < 9.8 mg/ml Positive skin prick test (SPT) to one or more of the 12 common aeroallergen extracts, defined as a wheal with an average diameter of > 3mm No other clinically significant abnormality on medical history and clinical examination Exclusion Criteria: Presence of antibodies directed against RV16 in serum (titer > 4), measured at visit 1 History of clinical significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness Women who are pregnant, lactating or who have a positive urine pregnancy test at visit 1 Chronic use of any other medication for treatment of lung disease other than short-acting beta2-agonists Participation in any clinical investigational drug treatment protocol within the preceding 3 months Ongoing use of tobacco products of any kind or previous usage with ≥ 6 total PY Concomitant disease or condition which could interfere with the conduct of the study, or for which the treatment might interfere with the conduct of the study, or which would, in the opinion of the investigator, pose an unacceptable risk to the patient People with young children (< 2 years)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mepolizumab<br> | Drug: Mepolizumab<br>* 3 monthly intravenous infusions of 750 mg<br>* Other names: Mepolizumab, SB240563;|
| Placebo Comparator: Saline<br> | Drug: Placebo<br>* 3 monthly intravenous infusions with saline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 | Change in pre-bronchodilator FEV1 between day 70 and day 77, i.e. 1 day prior and 6 days after RV16 challenge. | 1 day prior and 6 days after RV16 challenge | 
| Questionnaire to score asthma and common cold complaints |  | During 14 days following viral infection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral load | Viral load in nasal swab and bronchial brushes | Day 6 after viral infection | 
| Sputum eosinophils | Change in sputum eosinophils | Before and after mepolizumab infusion | 
| Cell influx in bronchoalveolar lavage fluid | Influx of neutrophils, eosinophils, macrophages, monocytes, T en B lymphocytes into the lungs | 6 days after viral infection | 
| Pro-inflammatory cytokines in bronchoalveolar lavage fluid | Measurement of IL-6, IL-8 and IFN-y in bronchoaveolar lavage fluid | 6 days after viral infection | 
| Antibody production | Anti RV-16 antibodies are measured in serum | 6 weeks after infection | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Asthma, Viral, Infection, Inflammation, Mepolizumab, Eosinophilia