Effect of Symbicort on GR Localisation in Asthma

Not Applicable

Completed

• Conditions: Asthma
• Interventions: Drug: Budesonide and Formoterol Product; Drug: Budesonide Powder; Drug: Placebos; Drug: Formoterol Inhalant Powder

• Registration Number: NCT00159263
• Lead Sponsor: Imperial College London

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.

Study Timeline

• Study Start: 2004-11
• Study First Submitted: 2005-09-08
• Study First Submitted QC: 2005-09-08
• Study First Posted: 2005-09-12
• Primary Completion: 2006-11
• Study Completion: 2006-11
• Results First Submitted: 2019-07-08
• Status Verified: 2019-09
• Results First Submitted QC: 2019-09-24
• Last Update Submitted: 2019-09-24
• Results First Posted: 2019-09-27
• Last Update Posted: 2019-09-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Budesonide/formoterol combination double	Budesonide and Formoterol Product	double 200/12 μg SYM200
Budesonide low dose	Budesonide Powder	Pulmicort(®) 200 μg
Budesonide high dose	Budesonide Powder	Pulmicort(®) 800 μg
Placebo	Placebos	placebo
Formoterol	Formoterol Inhalant Powder	Oxis(®) 12 μg
Budesonide/formoterol combination single	Budesonide and Formoterol Product	single 100/6 μg SYM100

Primary Outcome Measures

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

Trial Locations

Locations (1)

Section of Airway Disease, Asthma Lab, Imperial College London, Royal Brompton Hospital; 🇬🇧 London, United Kingdom