Omalizumab in Non-atopic Asthma

The Effect of a Humanised Monoclonal Anti-IgE Antibody,Omalizumab, on Disease Control and Bronchial Mucosal Inflammation in Non-atpic Asthma

Hypothesis- Omalizumab(humanized monoclonal anti-IgE antibody)improves disease control and reduces bronchial mucosal inflammation in non-atopic asthma.

In order to test the above hypothesis, the investigators propose a placebo controlled, double blind, parallel group study to obtain proof of principle that omalizumab exerts beneficial effects on disease control in non-atopic severe adult asthmatics aged 18-60 years . Forty patients will be randomized in a 1:1 ratio to receive omalizumab or matching placebo. Following 12 weeks of treatment with omalizumab/placebo, and as this treatment is continued for a further 8 weeks, anti-asthma treatment will be reduced. Dosages will be administered at 4 or 2 weekly intervals over a 16 week period (5 or 10 doses in total), which corresponds with the time stated as necessary to judge efficacy of therapy according to omalizumab's licensed indications in atopic asthma. Efficacy will be judged by clinical monitoring and by bronchial biopsy to assess effects on bronchial inflammation and local IgE production.

Study Overview

• Status: Unknown
• Conditions: Bronchial Asthma
• Intervention / Treatment: Drug: Omalizumab; Drug: Placebo

Detailed Description

The primary aim of the study is to obtain proof of principle that omalizumab therapy maintains lung function, symptom control and quality of life in a group of non-atopic, moderate/severe asthmatics whose regular anti-asthma therapy is uniformised and reduced for an 8 week period following omalizumab/placebo therapy while the latter therapy is continued.

A secondary aim is to see whether omalizumab, as compared with placebo therapy reduces bronchial inflammation and local IgE production in the bronchial mucosa of this same group of asthmatics.

Clinical outcome measures

The omalizumab and placebo treated groups will be compared for changes in the following clinical outcomes (for repeated measurements such as daily peak flow and symptoms the mean values of the first and last 10 days of the relevant study period will be compared).

1. prior to reduction of existing anti-asthma therapy (first 12 weeks of study):

   • Pre-bronchodilator FEV1 (primary outcome measure)
   • Morning and evening peak expiratory flow
   • Exhaled nitric oxide
   • Day and night time symptom scores
   • Total dosages of rescue beta2-agonist
   • Total symptom free days
   • Validated asthma Quality of Life scores

2. during anti-asthma therapy reduction phase (subsequent 8 weeks of study):

   • The primary outcome measure will be disease exacerbation, defined as a need for rescue oral corticosteroid medication for worsening of symptoms and/or deterioration in lung function, as agreed between the patient and the study physician
   • Secondary outcome measures will include all those measurements listed in section (a) above, unless they cannot be measured because of disease exacerbation (the primary outcome measure)

Laboratory outcome measures

These will arise from immunological, immunohistochemical and molecular analysis of peripheral blood and bronchial biopsies taken from all patients at the beginning and end of the first 12 weeks of the study prior to reduction of anti-asthma therapy and will comprise of changes in:

• Lay down of collagen types I, III, IV and V and tenascin
• Vascular structures and angiogenic stimuli (collagen type IV, CD31 and human VEGF (29,30)
• Inflammatory cells (eosinophils, T cells, B cells, plasma cells, macrophages, neutrophils, mast cells)
• Goblet cells will be stained using monoclonal anti-Muc-5AC antibody
• Immunoglobulin E and its high- and low-affinity receptors will be stained using specific monoclonal antibodies as in our previous studies. B cells (CD20+) and plasma cells (CD138+) will be examined for expression of free kappa and lambda IgE light chains using double, sequential IHC.

Staining analysis: Entire areas of stained biopsy sections will be subjected to image analysis using a Zeiss Vision KS300 system allowing objective, unbiased digital image analysis using a powerful macro language .

Cytokine and chemokine concentrations in endobronchial tissue homogenates: These will be measured in homogenates of 2 biopsies by electrochemiluminescence using the SECTOR Imager 6000 and assay kits produced by Meso Scale Discovery. The MS6000 Human TH1/TH2 10-Plex Base Kit will be used to measure IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, TNF-alpha. The MS6000 Human Chemokine 9-Plex Base Kit will be used to measure Eotaxin, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1beta, TARC.

IgE synthesis: Two biopsies from each patient will be snap frozen in RNA later for subsequent analysis of expression of switch circle transcripts and IgE mature and germline mRNA as in our previous recent publication and cloning of C-epsilon H-chain genes to look for evidence of clonal expansion of B cells caused by B cell superantigens. Two biopsies will be

\homogenised for extraction of B cells for cloning and analysis of IgE production by antigen microarray.

Serum: Stored serum samples taken at the time of bronchoscopy will be analysed for complete antigen-specific IgE repertoire using microarray, and anti-Fc-epsilon-RI activity using an in vitro basophil degranulation assay.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, E2 9JX
    • Not yet recruiting
    • London Chest Hospital
    • Contact: Neil Barnes, MD; Phone Number: 02089832433; Email: neil.barnes@bartsandthelondon.nhs.uk
    • Principal Investigator: Neil Barnes, MD
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's Hospital, London, UK
    • Contact: Christopher Corrigan, MD,PhD; Phone Number: 00-44-2071880610; Email: chris.corrigan@kcl.ac.uk
    • Contact: Prathap Pillai, MD; Phone Number: 00-44-2071880606; Email: prathap.pillai@kcl.ac.uk
    • Principal Investigator: Chris Corrigan, MD,PhD
    • Sub-Investigator: Prathap Pillai, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria-

• Males and females aged 18 to 60 years inclusive.
• Moderate or severe non-atopic asthma as defined below treated with inhaled corticosteroids for at least 6 months.
• Daytime and nighttime symptoms at least 3 days per week in the last 3 months prior to screening visit(despite taking inhaled corticosteroids with or without beta-2-agonists or leukotriene blockers.
• Pre-bronchodilator FEV1 40-80% of the predicted; reversibility equal to or more than 12% in response to inhaled beta-2-agonists documented at any time within the past 2 years.
• Negative skin prick and/or in vitro IgE tests to a range of 12 common aeroallergens(pollens:grass, hazel, alder, birch; danders: cat, dog; dust mite: D.pteronyssinus, D.farinae; moulds: Cladosporium, Aspergillus, Alternaria).

Exclusion Criteria

• Smoking within the past year or total smoking history more than 0.5 pack years.
• Pregnant or lactating females or those at risk of pregnancy.
• Treatment with more than 2000 mcg/day beclometasone, 1600 mcg/day budesonide or 1000 mcg/day fluticasone by inhalation or regular systemic corticosteroid at screening.
• Hospitalization for asthma or exacerbation requiring systemic corticosteroid therapy within 3 months of the screening visit.
• History of life threatening asthma, defined as an asthma episode that required intubations and/or was associated with hypercapnia, respiratory arrest and/or hypoxic seizures.
• Patients in whom, in the opinion of the study investigators, omalizumab therapy might normally require precaution (history of autoimmune disease, renal or hepatic impairment, hyperimmunoglobulin E syndrome, allergic bronchopulmonary aspergillosis and diabetes mellitus)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Omalizumab; There are 2 arms of the study; patients in one arm receiving omalizumab and in the other arm receiving placebo.	Drug: Omalizumab; Omalizumab or placebo by subcutaneous injections, at 4 weekly or 2 weekly intervals. Dosage is according to manufacturer's guidance and calculated based on body weight and total serum IgE.; Other Names: Xolair
PLACEBO_COMPARATOR: Placebo; There are 2 arms of the study; patients in one arm receiving omalizumab and in the other arm receiving placebo.	Drug: Placebo; Omalizumab or placebo by subcutaneous injections, at 4 weekly or 2 weekly intervals. Dosage is according to manufacturer's guidance and calculated based on body weight and total serum IgE.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre-bronchodilator FEV1	Prior to reduction of existing anti-asthma therapy (first 12 weeks of study): • Pre-bronchodilator FEV1 (primary outcome measure)	before and after treatment with omalizumab for 16 weeks
Disease exacerbation	During anti-asthma therapy reduction phase (subsequent 8 weeks of study): The primary outcome measure during asthma therapy reduction phase will be disease exacerbation defined as a need for rescue oral corticosteroid medication for worsening of symptoms and/or deterioration in lung function, as agreed between the patient and the study physician	From week 12 to week 20 of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day and night time symptom scores	These will be measured using standard Asthma Control Questionnaires(ACQ)	before and after treatment with omalizumab for 16 weeks
Morning and evening peakflows		before and after treatment with omalizumab for 16 weeks
Exhaled nitric oxide		before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)
Total dosage of rescue beta-2-agonists		before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)
Total symptom free days		before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)
Quality of life scores		before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)
Markers of airway remodelling and inflammation	These include- Collagen,tenascin,VEGF,CD31,inflammatory cells,goblet cells etc.	before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)
Local IgE synthesis in the bronchial mucosa and its expression	The measurement will include- IgE, its low and high affinity receptors, expression of free kappa and lambda light chains on B-cells and plasma cells	before and after treatment with omalizumab for 16 weeks(from week 0 to week 16)

Collaborators and Investigators

• Sponsor: King's College London
• Investigators: Principal Investigator: Christopher Corrigan, MD, PhD, King's College, London, UK; Principal Investigator: Neil Barnes, MD, London Chest Hospital, UK; Principal Investigator: Prathap Pillai, MD, King's College London

Publications and helpful links

General Publications

• Pillai P, Chan YC, Wu SY, Ohm-Laursen L, Thomas C, Durham SR, Menzies-Gow A, Rajakulasingam RK, Ying S, Gould HJ, Corrigan CJ. Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J. 2016 Dec;48(6):1593-1601. doi: 10.1183/13993003.01501-2015. Epub 2016 Oct 20.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ANTICIPATED): August 1, 2012

Study Registration Dates

• First Submitted: April 26, 2010
• First Submitted That Met QC Criteria: April 28, 2010
• First Posted (ESTIMATE): April 29, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): January 21, 2011
• Last Update Submitted That Met QC Criteria: January 20, 2011
• Last Verified: April 1, 2010

More Information

Terms related to this study

• Keywords: Allergy; Bronchial Asthma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Omalizumab
• Other Study ID Numbers: 09/H0804/43; 2009-009154-25 (EUDRACT_NUMBER)