Official Title: “The Pharmacokinetics and Anti-Inflammatory Effects of Prednisolone in Severe Asthma”

The purpose of the study is to evaluate whether severe asthmatic subjects have abnormal prednisolone absorption, and how this might affect the anti-inflammatory effects of prednisolone.

The main objectives are:

1. To evaluate blood prednisolone levels and their anti-inflammatory effects in two severe asthma groups, comparing patients on inhaled corticosteroids (ICS) alone to those on ICS plus oral prednisolone, and a group of well-controlled moderately severe asthmatics.

2. To evaluate if a 14-day course of prednisolone affects 'spot'(one-off) measurements of prednisolone levels, and if these are influenced by taking regular prednisolone

3. To determine the relationship between blood levels of prednisolone and its anti-inflammatory effects

Study Type: Interventional

Study Design: Other, Non-Randomized, Open Label, Single Group Assignment, Pharmacokinetics/Dynamics Study

Asthma is a disease characterized by reversible airways obstruction, bronchial hyper-responsiveness, and chronic inflammation of the bronchial mucosal lining. Currently over 5 million people (6-8% of the population) in the UK are receiving treatment for asthma.

Although most patients have mild-to-moderate asthma that is well-controlled by inhaled corticosteroids (ICS), in 5-10% of asthmatics, the disease is considered severe in that symptoms and control of asthma are largely unresponsive to treatment including systemic corticosteroids (CS). This subset of patients has greater morbidity and a disproportionate need for health care support in terms of use of drugs, admissions to hospital or use of emergency services, and time off work or school. Indeed, some severe asthma patients are also on oral CS in addition to ICS, and these patients are often described as being steroid-dependent since they need oral CS in addition to ICS to maintain their asthma control. Recent studies from our laboratory have shown that patients with severe asthma have relative corticosteroid resistance as measured by the responsiveness of peripheral blood mononuclear cells and alveolar macrophages to dexamethasone.

In asthma, corticosteroid- resistance (CSR) has usually been defined on the basis of changes in baseline FEV1 (forced expiratory volume in one second) after a 14-day course of oral prednisolone of 40mg/day; an increase of less than 15% of the baseline measurement, while demonstrating a greater than 15% improvements in FEV1 following inhaled β2-agonist, has been used. Patients who showed an improvement in FEV1 of 30% or more were considered as corticosteroid-sensitive (CSS). The arbitrary cut-off response of <15% response was chosen empirically without the knowledge of the distribution of responses to oral or inhaled CS.

CSR asthmatics are not completely resistant to the effects of corticosteroids, as stopping corticosteroid therapy leads to a clinical deterioration. It is not known at present whether the reduced corticosteroid responsiveness seen in severe asthma is genetically-determined or acquired, or both. Patient with CSR as defined above are not necessarily patients with severe asthma. The response of patients with severe asthma to a formal trial of oral prednisolone on lung function or inflammatory parameters has not been studied in detail. For example, it is not known whether the absorption of oral prednisolone which is commonly used to treat exacerbations of asthma is normal in patients with severe asthma. Pharmacokinetic studies have been reported in normal subjects and mild-moderate asthma, and also in CS-resistant asthmatics, and 'normal' pharmacokinetics has been reported in the latter groups. However, we need to exclude this as a potential course of relative CS-resistance in severe asthma.

Corticosteroids are known to exert anti-inflammatory effects as assessed in bronchial biopsies, which is the basis of its beneficial effects in asthma. These effects can also be assessed non-invasively using measurements of exhaled nitric oxide (eNO) or induced sputum eosinophil counts. The effect of a prednisolone trial on these measurements has not been performed. We have previously shown the value of measuring IL-8 release from whole blood as a marker of the inflammatory response. Serum IL-8 and TNF-α have been found to be higher in severe asthmatics than in the mild-moderate asthmatics. Therefore, we propose to study the response of patients with severe asthma to oral prednisolone, looking at drug levels and their anti-inflammatory effects. Anecdotally, we have found that many of our severe asthmatic patients have low prednisolone levels, even though they have been compliant with their medication. Spot levels of prednisolone (one-off measurements of blood levels) are used to check compliance. The effect of continuous oral therapy on prednisolone levels and its suppression of inflammation is unknown. It has been previously postulated that such therapy may lead to a reduction in the effectiveness of corticosteroids as an anti-inflammatory agent. Therefore, we propose to study two groups of patients with severe asthma, those on ICS alone and those on ICS plus a maintenance dose of prednisolone ranging 5-20 mg/day; the control group would be moderately-severe asthmatics who are well controlled on ICS.

The patients will be given a fourteen-day course of daily 40mg of prednisolone (non enteric-coated tablets). The study protocol is summarized below. Subjects will attend the Asthma Lab at the Royal Brompton Hospital for screening. They will keep peak expiratory flow rate (PEFR) and symptom diary cards for 2 weeks prior to and during the two week course of prednisolone. Patients already on prednisolone will have the maintenance dose increased to 40mg.

On Visits 2 and 4, patients will be fasting overnight and will have the blood tests at time 0 hours. They will then take the prednisolone with or after having their breakfast. Sputum and blood samples will be taken, spirometry and exhaled nitric oxide measured at various time intervals as specified in the protocol.

Summary of Study Protocol:

Visit 1 - screening visit - History and examination - Spirometry pre and post β agonist - Exhaled nitric oxide (eNO) - Blood test for prednisolone and cortisol levels - Issue diary cards

Visit 2 - Day 1: an intravenous cannula will be sited to allow for repeated blood sampling at 0, 1, 2, 3, 4, 5 and 6 hours post prednisolone dose

1. Time 0 hours (pre prednisolone): - Blood test for full blood count (FBC), prednisolone/cortisol levels, inflammatory mediator assay - Complete Asthma control questionnaire - eNO - Spirometry - Induced sputum

2. Subject to take 40mg prednisolone; at 1,2,3 4 and 5 hours post dose: - eNO - blood test for prednisolone/cortisol levels, inflammatory mediator assay

3. 6 hours post prednisolone: - Blood test for full blood count, prednisolone/cortisol levels, inflammatory mediator assay - eNO - Spirometry pre and post β-agonist

Visit 3 - Day 2: 24 hours post first dose (pre 2nd dose) - Take blood for FBC, prednisolone/cortisol levels, inflammatory mediator assay - Measure eNO - Spirometry pre and post β agonist - Induced sputum

Visit 4 - Day 14 (last day of 40mg prednisolone): repeat protocol as for visit 2

Visit 5 - Day 15 (24 hours after last 40mg prednisolone); collect diary cards - Take blood for FBC, prednisolone/cortisol levels, inflammatory mediator assay - Measure eNO - Spirometry pre and post β agonist - induced sputum

Primary:

• serum prednisolone levels over 24 hours 14 days No
• change in FEV1 24 hours post prednisolone 14 days No
• changes in eNO, sputum eosinophils and inflammatory mediators over 24 hours 14 days No

Secondary:

• difference between day 1 and day 14 in serum prednisolone levels 14 days No
• difference in FEV1 between day 1 and day 14 14 days No
• difference in inflammatory markers between day 1 and day 14 14 days No
• changes in asthma control symptoms before and after treatment 14 days No

Inclusion Criteria:

• for severe asthmatics:
• Physician diagnosis of asthma
• Aged 18 - 70
• Non-smokers or ex-smokers with less than 5 pack/year history
• 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
• for moderately-severe asthma:
• Physician diagnosis of asthma
• Aged 18 - 70
• Non-smokers or ex-smokers with less than 5 pack/year history
• Less than 2 courses of prednisolone per year
• Taking up to 2000 mcg of inhaled corticosteroid (BDP equivalent) per day
• Stable asthma for at least 6 months prior to enrollment

Exclusion Criteria:

• Current smokers, or less than 3 years since quitting smoking
• Less than 4 weeks from an exacerbation
• Diabetes
• Active peptic ulceration
• Previous history of psychiatric disturbances on high dose prednisolone
• On steroid-sparing agent or immunosuppressant such as azathioprine, methotrexate and ciclosporin
• Concomitant anti-IgE therapy
• Pregnancy

Lead Sponsor: Imperial College London

Asthma Laboratory, Royal Brompton Hospital

London  SW3 6LY United Kingdom

Overall Clinical Trial Officials and Contacts

Kian F Chung Principal Investigator Imperial College London  

Overall Contact: Patricia Macedo 02-07-351-8051 p.macedo@imperial.ac.uk

Information obtained from ClinicalTrials.gov on July 23, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00662298

Study ID Number: 2007-002084-27

ClinicalTrials.gov Identifier: NCT00662298

Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency