Clinical trial NCT00159263: Effect of Symbicort on GR Localisation in Asthma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Asthma
Keywords: Asthma
Glucocorticoid
Long-acting beta2-adrenoceptor
Inhaled corticosteroids
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2005-09-12
Enrollment: 10
Sex: ALL
Minimum age (years): 21
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in GR-GRE Binding
timeFrame: 1-2h
measure: Changes in MKP-1 mRNA
timeFrame: 1-2h
measure: IL8 mRNA
timeFrame: 1-2h
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Section of Airway Disease, Asthma Lab, Imperial College London, Royal Brompton Hospital
Study officials:
affiliation: Imperial College London
name: Sergei A Kharitonov, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Essilfie-Quaye S, Ito K, Ito M, Kharitonov SA, Barnes PJ. Comparison of Symbicort(R) versus Pulmicort(R) on steroid pharmacodynamic markers in asthma patients. Respir Med. 2011 Dec;105(12):1784-9. doi: 10.1016/j.rmed.2011.08.020. Epub 2011 Sep 7.