Asthma
Conditions
Keywords
Asthma, Glucocorticoid, Long-acting beta2-adrenoceptor, Inhaled corticosteroids
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.
Interventions
DRUGPlacebos
Dry powder inhaler
DRUGFormoterol Inhalant Powder
12ug
Inhaler
DRUGBudesonide and Formoterol Product
Combination Inhaler, Symbicort
Sponsors
AstraZeneca
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Changes in MKP-1 mRNA | 1-2h | Changes in MKP-1 mRNA measured by PCR |
| IL8 mRNA | 1-2h | Measured by PCR |
Countries
United Kingdom
Participant flow
Recruitment details
10patient recruited mild asthma
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Crossover study, same volunteers in all arm, received the following interventions: formoterol, Budesonide low and high dose, or combination of these | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Overall Study | — |
|---|---|---|
| Age, Continuous | 33 years STANDARD_DEVIATION 3 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 10 participants | — |
| Sex: Female, Male Female | 6 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
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
Time frame: 1-2h
Population: Crossover, each patient had all treatments
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Changes in GR-GRE Binding | 1.4 GRE activity (OD) |
| Formoterol | Changes in GR-GRE Binding | 1.4 GRE activity (OD) |
| Budesonide Low Dose | Changes in GR-GRE Binding | 1.6 GRE activity (OD) |
| Budesonide High Dose | Changes in GR-GRE Binding | 2.3 GRE activity (OD) |
| Budesonide/Formoterol Combination Single | Changes in GR-GRE Binding | 3.5 GRE activity (OD) |
| Budesonide/Formoterol Combination Double | Changes in GR-GRE Binding | 3 GRE activity (OD) |
p-value: 0.04ANOVA
Primary
Changes in MKP-1 mRNA
Changes in MKP-1 mRNA measured by PCR
Time frame: 1-2h
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Changes in MKP-1 mRNA | 1 MKP1/GNB2L1 ratio |
| Formoterol | Changes in MKP-1 mRNA | 3 MKP1/GNB2L1 ratio |
| Budesonide Low Dose | Changes in MKP-1 mRNA | 3 MKP1/GNB2L1 ratio |
| Budesonide High Dose | Changes in MKP-1 mRNA | 4 MKP1/GNB2L1 ratio |
| Budesonide/Formoterol Combination Single | Changes in MKP-1 mRNA | 5 MKP1/GNB2L1 ratio |
| Budesonide/Formoterol Combination Double | Changes in MKP-1 mRNA | 5 MKP1/GNB2L1 ratio |
p-value: 0.01ANOVA
Primary
IL8 mRNA
Measured by PCR
Time frame: 1-2h
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | IL8 mRNA | 1 IL8/GNB2L1 ratio |
| Formoterol | IL8 mRNA | 4 IL8/GNB2L1 ratio |
| Budesonide Low Dose | IL8 mRNA | 4 IL8/GNB2L1 ratio |
| Budesonide High Dose | IL8 mRNA | 0.4 IL8/GNB2L1 ratio |
| Budesonide/Formoterol Combination Single | IL8 mRNA | 0.2 IL8/GNB2L1 ratio |
| Budesonide/Formoterol Combination Double | IL8 mRNA | 0.2 IL8/GNB2L1 ratio |
p-value: 0.04ANOVA