p38 Mitogen−Activated Protein Kinase (MAPK) and Steroid Insensitivity in Asthma - Full Text View

Sponsor:	Imperial College London
Collaborators:	Royal Brompton & Harefield NHS Foundation Trust Medical Research Council
Information provided by:	Imperial College London
ClinicalTrials.gov Identifier:	NCT00676572

Purpose

This research aims to find out how the inflammation in patients suffering from severe asthma is different from that in non−severe asthma, and how it may prevent corticosteroids from working efficiently in severe asthma.

It will look,in particular, at a protein enzyme called p38 mitogen−activated protein kinase (p38 MAPK for short)which controls the activation of several important pathways in the cell. We wish to find out whether this enzyme is more active in cells obtained from patients with severe asthma compared to those with non−severe asthma. We would like to understand how this enzyme can cause the cell to respond less well to the anti−inflammatory effects of corticosteroids. We also wish to find out whether any specific inhibitors of p38 MAPK can improve severe asthma by improving the effects of corticosteroids on these cells.

We hypothesise that activation of the intracellular MAPK signalling pathway underlies the inflammatory processes of severe asthma, and leads to the diminution of the anti-inflammatory actions of CS through histone modification.

Condition	Intervention
Asthma	Other: Fiberoptic bronchoscopy; blood test

Study Type:	Observational
Study Design:	Time Perspective: Prospective
Official Title:	p38 MAPK Activation as the Basis for Corticosteroid Insensitivity in Severe Asthma

Resource links provided by NLM:

MedlinePlus related topics: Asthma

U.S. FDA Resources

Further study details as provided by Imperial College London:

Primary Outcome Measures:

1. Differences in activity and downstream activity of the p38 MAPK activity in macrophages or PBMCs between those from severe and non−severe asthmatics [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Differences in the effect of p38 MAPK inhibitor in dexamethasone−inhibition of cytokine release from alveolar macrophages and PBMCs between severe and non−severe asthmatics [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Biospecimen Retention: Samples With DNA

sputum cell pellets and supernatant; BAL supernatant; endobronchial biopsies; smooth muscle cell culture from biopsies

Estimated Enrollment:	120
Study Start Date:	May 2008
Estimated Study Completion Date:	May 2012
Estimated Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
Severe asthma	Other: Fiberoptic bronchoscopy; blood test Fiberoptic bronchoscopy for obtention of alveolar macrophages and bronchial biopsies for histology and culture of airway smooth muscle cells
Non-severe asthma	Other: Fiberoptic bronchoscopy; blood test Fiberoptic bronchoscopy for obtention of alveolar macrophages and bronchial biopsies for histology and culture of airway smooth muscle cells

Detailed Description:

DESIGN Comparative study to analyse differences in the characteristics of lung macrophages and blood monocytes between non-severe and severe asthmatics.

AIMS

To determine whether there are differences in terms of cell expression and activation between lung macrophages and blood monocytes from non-severe and severe asthma
To determine the mechanisms of the lung macrophage and blood monocyte relative resistance to the effect of corticosteroids in severe asthma, and particularly focus on the role of p38 MAPK
To determine the differences in airway smooth muscle cells between non-severe and severe asthma

OUTCOME MEASURES

Clinically the differences in inflammatory and remodelling markers between non-severe and severe asthma
Differences in histone phosphorylation, NF-kB activity and glucocorticoid receptor activation and actions in macrophages and monocytes between non- severe and severe asthma
Differences in behaviour of airway smooth muscle cells cultured from biopsies obtained from non-severe and severe asthma

Severe and non-severe asthmatic subjects will be classified following ATS criteria. They undergo spirometry with reversibility testing, PC20, skin prick tests, exhaled nitric oxide measurements and induced sputum. They will have blood taken for PBMCs and undergo fiberoptic bronchoscopy for obtention of alveolar macrophages and bronchial biopsies

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Asthmatic subjects will be recruited from asthma clinics at the Royal Brompton Hospital and from primary care clinics.

Criteria

Inclusion Criteria:

Age 18-60
Physician diagnosis of asthma

Non-severe asthmatic subjects:

mild to moderately severe asthma.
The groups will be defined as follows, according to their need for treatments (as established in the Asthma Management GINA or BTS guidelines):
1. Mild: intermittent symptoms and need for reliever bronchodilator less than once a day
2. moderate asthma: well-controlled asthma with minimal symptoms while on inhaled corticosteroid therapy not exceeding 2,000 μg beclomethasone equivalent.

Severe asthmatic subjects:

will have at least 1 major and 2 minor criteria (as below) Major characteristics (at least one of the following criteria)
- Treatment with continuous or near continuous (>50% of year) oral corticosteroids
- Requirement for treatment with high dose inhaled corticosteroids (ICS) Minor characteristics (at least 2 out of the following)
  1. Requirement for daily treatment with a controller medication in addition to ICS e.g. LABA, theophylline, leukotriene antagonist
  2. Asthma symptoms requiring SABA on a daily or near daily basis
  3. Persistent airways obstruction (FEV1 <80% predicted, diurnal PEF variation >20%)
  4. One or more emergency care visits for asthma per year
  5. 3 or more steroid "bursts" per year
  6. Prompt deterioration with ≤ 25% reduction in oral or ICS
  7. Near fatal asthma event in the past

Exclusion Criteria:

Current smokers, or less than 3 years since quitting smoking (< 5 pack/years)
Less than 4 weeks from an exacerbation
On steroid-sparing agent or immunosuppressant such as azathioprine, methotrexate and ciclosporin
Concomitant anti-IgE therapy
On anti-platelet or anti-coagulant drugs
Low platelet count
Pregnancy or breast-feeding
Intubation for asthma within 6 months of entry into this study (if undergoing bronchoscopy)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00676572

Contacts

Contact: Kian F Chung, MBBS MD FRCP DSc

207-351-8995

f.chung@imperial.ac.uk

Locations

United Kingdom
Asthma Laboratory, Royal Brompton Hospital, Sydney Street	Recruiting
London, United Kingdom, SW3 6NP
Contact: Florence Chow, RGN 207-351-8051 florence.chow@imperial.ac.uk
Sub-Investigator: Patricia Macedo, MBBS MRCP MSc

Sponsors and Collaborators

Imperial College London

Royal Brompton & Harefield NHS Foundation Trust

Medical Research Council

Investigators

Principal Investigator:	Kian F Chung, MBBS MD FRCP DSc	Imperial College London
Principal Investigator:	Pankaj Bhavsar, BSc PhD	Imperial College London

More Information

No publications provided

Responsible Party:	Professor K F Chung, Imperial College London
ClinicalTrials.gov Identifier:	NCT00676572 History of Changes
Other Study ID Numbers:	08/H0708/29, CRO1014
Study First Received:	May 8, 2008
Last Updated:	June 22, 2011
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency; United Kingdom: Research Ethics Committee

Keywords provided by Imperial College London:

severe asthma
corticosteroid insensitivity

Additional relevant MeSH terms:

Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases

Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases

ClinicalTrials.gov processed this record on February 12, 2012