Mepolizumab Treatment for Rhinovirus-induced Asthma Exacerbations (MATERIAL)

The Efficacy of Mepolizumab Treatment on Rhinovirus Induced Asthma Exacerbations

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

Study Overview

• Status: Unknown
• Conditions: Asthma; Viral Infection
• Intervention / Treatment: Drug: Mepolizumab; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Suzanne M Bal, PhD; Phone Number: +31 205668043; Email: s.m.bal@amc.uva.nl
• Study Contact Backup: Name: Koenraad F van der Sluijs, PhD; Phone Number: +31 205668224; Email: kvandersluijs@amc.uva.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Recruiting
    • Academic Medical Center
    • Principal Investigator: René Lutter, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline	Drug: Placebo; 3 monthly intravenous infusions with saline
Experimental: Mepolizumab	Drug: Mepolizumab; 3 monthly intravenous infusions of 750 mg; Other Names: Mepolizumab, SB240563

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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: GlaxoSmithKline; The Netherlands Asthma Foundation
• Investigators: Principal Investigator: René Lutter, PhD, Academic Medical Center, Respiratory Medicine; Study Director: Elisabeth H Bel, MD, PhD, Academic Medical Center, Respiratory Medicine; Study Director: Peter J Sterk, PhD, Academic Medical Center, Respiratory Medicine

Publications and helpful links

General Publications

• 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. Erratum In: N Engl J Med. 2011 Feb 10;364(6):588.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): March 1, 2014

Study Registration Dates

• First Submitted: January 25, 2012
• First Submitted That Met QC Criteria: January 25, 2012
• First Posted (Estimate): January 27, 2012

Study Record Updates

• Last Update Posted (Estimate): February 7, 2012
• Last Update Submitted That Met QC Criteria: February 6, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Inflammation; Infection; Asthma; Mepolizumab; Eosinophilia; Viral
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Virus Diseases; Asthma
• Other Study ID Numbers: MATERIAL