Effect of Symbicort on GR Localisation in Asthma

Study Overview
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Brief Summary
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To investigate a possible interaction between formoterol and budesonide on GR-translocation and to compare the effect of different doses of Symbicort (80/4.5 and 2x80/4.5 mcg) with the effect of budesonide (200 mcg and 800 mcg) on GR translocation, and to investigate the effect of the study drugs on exhaled NO (bronchial and alveolar fraction.

Detailed Description
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Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophage. In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR.

Official Title
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Effect of Symbicort on GR (Glucocorticoid Receptor) Translocation in Induced Sputum in Comparison With Budesonide, Formoterol and Placebo. A Single Dose Exploratory Study in Patients With Mild Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebos
* Drug: Formoterol Inhalant Powder
* Drug: Budesonide Powder
* Drug: Budesonide and Formoterol Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with mild steroid-naïve asthma (ATS criteria) of either sex with FEV1 >70 % pred Able to produce sputum after sputum induction Exhaled NO (flow 50 ml/s) ≥ 20 ppb Written informed consent Exclusion Criteria: Current upper respiratory tract infections Use of inhaled and/or oral GCS within 4 weeks prior to visit 1 Treatment with antileukotrienes, theophylline, tiotropium and ipratropium within 2 weeks prior to screening visit Hypersensitivity to any of the investigational drugs or lactose Use of any beta blocking agent (including eye-drops) Women who are pregnant, breast-feeding or planning a pregnancy during the study. Women must be postmenopausal (at least one year must have passed after the last menstruation), surgically sterile or using acceptable contraceptives, as judged by the investigator Any significant disease or disorder (e.g. cardiovascular, pulmonary (other than asthma), gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the results of the study, or the subjects ability to participate in the study Inability to tolerate temporary withdrawal of bronchodilatory therapy Subjects not considered capable, as judged by the investigator, of following instructions of the study, e.g. because of a history of alcohol or drug abuse or any other reason Previous randomization in this study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo | Drug: Placebos<br>* Dry powder inhaler<br>|
| Experimental: Formoterol<br>Oxis(®) 12 μg | Drug: Formoterol Inhalant Powder<br>* 12ug<br>* Other names: Oxis;|
| Experimental: Budesonide low dose<br>Pulmicort(®) 200 μg | Drug: Budesonide Powder<br>* Inhaler<br>* Other names: Pulmicort;|
| Experimental: Budesonide high dose<br>Pulmicort(®) 800 μg | Drug: Budesonide Powder<br>* Inhaler<br>* Other names: Pulmicort;|
| Experimental: Budesonide/formoterol combination single<br>single 100/6 μg SYM100 | Drug: Budesonide and Formoterol Product<br>* Combination Inhaler, Symbicort<br>* Other names: Combination Inhaler, Symbicort;|
| Experimental: Budesonide/formoterol combination double<br>double 200/12 μg SYM200 | Drug: Budesonide and Formoterol Product<br>* Combination Inhaler, Symbicort<br>* Other names: Combination Inhaler, Symbicort;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in GR-GRE Binding | The GR-GRE binding is the glucocorticoid receptor (GR) DNA binding affinity. GR-GRE activity as assed by enzyme-immunosorbent assay | 1-2h | 
| Changes in MKP-1 mRNA | Changes in MKP-1 mRNA measured by PCR | 1-2h | 
| IL8 mRNA | Measured by PCR | 1-2h | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Glucocorticoid, Long-acting beta2-adrenoceptor, Inhaled corticosteroids