Inflammation and Corticosteroid Responsiveness in Severe Asthma

NCT ID: NCT00180661

Last Updated: 2019-10-04

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 39 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2003-08-31
• Study Completion Date: 2008-05-31

Brief Summary

Some patients with mild asthma may develop severe asthma. It is not known what makes patients with mild asthma become severe, and we plan to find out why this happens. Patients with severe asthma may have a different type of inflammation in the airway tubes. Patients with severe asthma do not get as much benefit from taking steroid inhalers or tablets compared to asthma patients with mild disease. The study hypothesis is that the inflammation in severe asthma is such that it makes steroids less effective in treating asthma. We will find out what possible abnormalities there are in the blood cells and the bronchoalveolar macrophage cells in the lungs of patients with severe asthma compared to those with mild or moderate asthma.

Detailed Description

Study Design Patients referred to the Royal Brompton Hospital with severe asthma will be entered into a protocol that will determine whether they have asthma, and if so, the severity and clinical features of their asthma. Patients will also undergo investigations relating to asthma as detailed below. We will use an agreed Severe Asthma Research protocol (SARP) screening system to diagnose asthma (history, bronchodilator response and presence of bronchial hyperresponsiveness) (Screening questionnaire in SARP Handbook). Usually, the protocol will be carried out while the patient is admitted over 3-night admission.

Patients will undergo fiberoptic bronchoscopy. We will obtain cells by bronchoalveolar lavage and bronchial biopsies of the airway mucosa. These cells and biopsies will be studied in vitro as to the expression of corticosteroid receptor nuclear translocation, expression of cytokines, and the degree of histone acetylation/deacetylation status. These findings will be compared to those cells and biopsies obtained from mild and moderately severe asthma.

In a subgroup of patients with severe asthma, patients will be treated with oral prednisolone 40 mg/day or increase in maintenance dose of prednisolone by 40 mg/day. Fiberoptic bronchoscopy will then be repeated.

Details of the interventions proposed Some of the interventions listed below are in routine clinical use for investigation of severe asthma. For example, the computed tomogram is only ordered on clinical grounds. A fiberoptic bronchoscopy will be performed.

1. Demographic history and history of their symptoms of asthma and treatments using a comprehensive questionnaire

2. Quality of life questionnaire (AQLQ)

3. Skin prick tests to 16 common allergens

4. Measuring lung function tests

5. Bronchial responsiveness to methacholine

6. Bronchial reversibility test to inhaled salbutamol

7. Keeping a diary card of symptoms, treatments and peak flows for 2 weeks

8. Observance of compliance to treatments

9. Provision of sample of sputum, spontaneous or induced

10. Measuring exhaled nitric oxide; collecting of exhaled breath condensates

11. Fiberoptic bronchoscopy to obtain bronchoalveolar lavage cells, bronchial brushings and bronchial biopsies

12. Obtaining sample of blood for DNA extraction for genetic analysis

13. Obtaining blood for blood mononuclear cells for in vitro analysis of the effects of corticosteroids In patients with mild-to-moderate asthma, test 8 will not be performed. The details of these interventions are enclosed in the SARP Handbook.

Sources and Recruitment of Subjects:

Patients will be recruited from all patients referred to the Royal Brompton Hospital with a referral diagnosis of severe or difficult asthma for further management. The Royal Brompton Hospital is recognized nationally as a center for referral of such patients.

7Inclusion criteria The final diagnosis of severe asthma will be made according to the screening steps we have set up. The definition will require the presence of one or both major criteria (treatment with continuous or near continuous oral corticosteroids and/or requirement for treatment with high dose inhaled steroids) and two minor criteria.

Patients who do not fit the criteria of severe asthma will not be entered into the study.

Age 18-60; both sexes.

For the investigation of fiberoptic bronchoscopy, other additional inclusion criteria will be imposed:

1. Post-bronchodilator FEV1 greater than 40% on the day of the bronchoscopy

2. No evidence of an exacerbation of asthma within the past 4 weeks.

3. Ability to cooperate with procedures

4. Ability to give consent

5. The bronchoscopist has determined the subject is clinically appropriate for bronchoscopy

Patients will be excluded for fiberoptic bronchoscopy if:

1. FEV1 is less than 35% predicted before or less than 40% predicted after bronchodilator administration

2. Asthma is clinically unstable

3. Communication channels is not established for follow-up contacts

4. Clinically significant, unstable co-morbidities are present

Exclusion criteria Current smokers, and ex-smokers with greater than 10 pack years history of smoking.

Pregnancy or unreliable contraceptive measures in child-bearing woman.

Volunteer subjects We will need comparative asthmatic subjects with 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): (i) Mild: intermittent symptoms and need for reliever bronchodilator less than once a day; (ii) moderate asthma: well-controlled asthma with minimal symptoms while on inhaled corticosteroid therapy not exceeding 2,000 microgram beclomethasone equivalent .

These patients will be recruited from the Asthma clinics attending the Royal Brompton Hospital, and also the milder patients will be recruited by advertisement within the Hospital, or from local general practices.

Current involvement in research The patients entered into this study will not be involved in any other research project, and must have Completed any other project within a month of entry into the current study. From previous experience, we aim to recruit 12 patients with severe asthma per year; in total, 50 patients with severe asthma over a 4 year period. Concomitantly, we will recruit 40 mild-to-moderately severe asthma patients. Pharmacology and Dispensing (i) substance: Prednisolone tablets (ii) route of administration: Oral (iii) frequency : once a day (iv) dosage: 30 mg/day (or addition of 30 mg on top of maintainence dose) (v) stage of CSM evaluation: n/a.

Conditions

Asthma

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Severe Asthma

Patients under Steps 4/5 of Asthma Treatment - SIGN/BTS Guidelines

No interventions assigned to this group

Moderate Asthma

Asthma patients on steps 2/3 of Asthma treatment according to SIGN/BTS Guidelines

No interventions assigned to this group

Mild Asthma

Asthma patients on steps 1 of asthma treatment (steroid naive).

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

The final diagnosis of severe asthma will be made according to the screening steps we have set up. The definition will require the presence of one or both major criteria (treatment with continuous or near continuous oral corticosteroids and/or requirement for treatment with high dose inhaled steroids) and two minor criteria.

Patients who do not fit the criteria of severe asthma will not be entered into the study.

Age 18-60; both sexes.

1. Post-bronchodilator FEV1 greater than 40% on the day of the bronchoscopy

2. No evidence of an exacerbation of asthma within the past 4 weeks.

3. Ability to cooperate with procedures

4. Ability to give consent

5. Current smokers, and ex-smokers with greater than 10 pack years history of smoking.

Exclusion Criteria

Pregnancy or unreliable contraceptive measures in child-bearing woman. he bronchoscopist has determined the subject is clinically appropriate for bronchoscopy

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• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Fan Chung

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kian Fan Chung, MD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Royal Brompton Hospital

London, , United Kingdom

Countries

United Kingdom

References

Chung KF, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, Bel E, Burney P, Chanez P, Connett G, Corrigan C, de Blic J, Fabbri L, Holgate ST, Ind P, Joos G, Kerstjens H, Leuenberger P, Lofdahl CG, McKenzie S, Magnussen H, Postma D, Saetta M, Salmeron S, Sterk P. Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society. Eur Respir J. 1999 May;13(5):1198-208. doi: 10.1034/j.1399-3003.1999.13e43.x. No abstract available.

Reference Type: BACKGROUND

PMID: 10414427 (View on PubMed)

Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008 Sep;63(9):784-90. doi: 10.1136/thx.2007.090027. Epub 2008 May 20.

Reference Type: RESULT

PMID: 18492738 (View on PubMed)

Other Identifiers

HL-69155

Identifier Type: -

Identifier Source: org_study_id