Clinical trial NCT01520051: Mepolizumab Treatment for Rhinovirus-induced Asthma Exacerbations
Official title: The Efficacy of Mepolizumab Treatment on Rhinovirus Induced Asthma Exacerbations
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Asthma
Viral Infection
Keywords: Asthma
Viral
Infection
Inflammation
Mepolizumab
Eosinophilia
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: The Netherlands Asthma Foundation
name: GlaxoSmithKline
First posted: 2012-01-27
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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:

1. Reduces virus-induced bronchial inflammation
2. Attenuates virus-induced asthma symptoms, airflow limitation and bronchial hyperresponsiveness.
3. Enhances cellular immune responses to the virus.

The aims of this study are to:

1. To investigate whether IL-5 neutralization reduces the inflammatory response to viral airway infections in allergic asthma patients
2. To investigate whether IL-5 neutralization prevents or reduces asthma symptoms during virus-induced asthma exacerbations
3. 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.

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)

Primary outcomes:
measure: FEV1
timeFrame: 1 day prior and 6 days after RV16 challenge
measure: Questionnaire to score asthma and common cold complaints
timeFrame: During 14 days following viral infection
Secondary outcomes:
measure: Viral load
timeFrame: Day 6 after viral infection
measure: Sputum eosinophils
timeFrame: Before and after mepolizumab infusion
measure: Cell influx in bronchoalveolar lavage fluid
timeFrame: 6 days after viral infection
measure: Pro-inflammatory cytokines in bronchoalveolar lavage fluid
timeFrame: 6 days after viral infection
measure: Antibody production
timeFrame: 6 weeks after infection
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
Study officials:
affiliation: Academic Medical Center, Respiratory Medicine
name: René Lutter, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Academic Medical Center, Respiratory Medicine
name: Elisabeth H Bel, MD, PhD
role: STUDY_DIRECTOR
affiliation: Academic Medical Center, Respiratory Medicine
name: Peter J Sterk, PhD
role: STUDY_DIRECTOR
References:
citation: Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985-93. doi: 10.1056/NEJMoa0805435.
citation: Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009 Mar 5;360(10):973-84. doi: 10.1056/NEJMoa0808991.
citation: Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000 Dec 23-30;356(9248):2144-8. doi: 10.1016/s0140-6736(00)03496-6.
citation: Message SD, Laza-Stanca V, Mallia P, Parker HL, Zhu J, Kebadze T, Contoli M, Sanderson G, Kon OM, Papi A, Jeffery PK, Stanciu LA, Johnston SL. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13562-7. doi: 10.1073/pnas.0804181105. Epub 2008 Sep 3.