Effect of Symbicort ® on GR in Sputum in COPD
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|ClinicalTrials.gov Identifier: NCT01787097|
Recruitment Status : Completed
First Posted : February 8, 2013
Last Update Posted : August 27, 2015
The purpose of the research (or "knowledge gap" this research is designed to fill) is to understand the science of how the combination therapy of 2 drugs (inhaled longacting beta-agonists(LABA) and inhaled corticosteroids (ICS), which are commonly used in chronic obstructive pulmonary disease (COPD) patients, is better than each drug alone. ICS and LABA both have antiinflammatory properties; that is, they dampen the inflammation in the cells of the airways in the lungs. The combination of LABA and ICS has also been shown to improve clinical effectiveness in asthma patients. The addition of a LABA to LOW doses of ICS has been shown to be more clinically beneficial in asthma than the use of HIGH doses of ICS alone. This has allowed a reduction in the total ICS dose and minimised the adverse side effects of inhaled corticosteroids. Recent evidence suggests that the use of combination therapy of LABA and ICS may also improve clinical effectiveness in COPD patients.
Investigators will address this hypothesis by examining the inflammation cells of COPD direct from the site of disease (the airways) by looking at sputum/mucus. This research will build on the existing knowledge of the science of how these drugs work in asthma and COPD and allows us to understand the molecular science, which may support new future drug targets for patients with COPD, which are greatly needed.
|Condition or disease||Intervention/treatment||Phase|
|Chronic Obstructive Lung Disease||Drug: Symbicort®, Formoterol, Budesonide||Phase 4|
Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR). The inactive GR is bound to a protein complex that includes heat shock protein hsp90, acting as molecular chaperones to prevent the nuclear localisation of unoccupied GR.
GR binding to the palindromic promotor induces the transcriptional induction of anti-inflammatory genes such as mitogen-activated protein kinase phosphatase-1 (MKP-1) and secretory leukocyte protease inhibitor (SLPI). GR-steroid complex also binds to negative GRE sequences, resulting in inhibition of pro-inflammatory mediators, such as IL-6. More importantly, GR binds transcription factor with recruitment of histone deacetylase (HDAC) and inhibits wide range of pro-inflammatory cytokines. By this process of transrepression, corticosteroids reduce such pro-inflammatory cytokines as tumour necrosis-alpha (TNF-alpha) and interleukin-8 (IL-8) in asthmatic patients whereas they are far less effective in chronic obstructive pulmonary disease (COPD) patients.
The combination of inhaled corticosteroids (ICS) and long acting beta 2-agonists (LABAs) has been shown to improve clinical effectiveness and anti-inflammatory properties in asthma. The addition of a LABA to low dose ICS has been shown to be more clinically beneficial in asthma than the use of high dose ICS, allowing a reduction in ICS dose and minimising and adverse side effects of corticosteroids. Recent evidence suggests that this may also be the case in COPD.
ICS such as budesonide, beclomethasone and fluticasone have been used in combination with LABA's such as formoterol and salmeterol. These combination treatments are established in national guidelines for treating patients with asthma and also, COPD. The combination of formoterol and budesonide (Symbicort ®, Astra Zeneca) will be studied in this project.
Evidence suggests that LABAs enhance GR function in vitro. In an asthmatics study, the combination of formoterol and budesonide (Symbicort ®, Astra Zeneca) was as effective as high dose ICS on GR activation, gene transactivation and transrepression. However, the precise mechanisms for this enhanced effectiveness are unknown, although priming of the steroid receptor (GR) by LABAs may be important.
Investigators have developed a novel method of measuring GR-GRE binding activity in sputum using an enzyme immunosorbent assay system. This method, together with the measurements of some functional readouts, will help us to understand some of the mechanisms of steroid and GR interactions using non-invasive methods of assessment of the airways. This may provide insight into the mechanisms of corticosteroid action and whether the addition of a LABA to ICS can alter molecular patterns, which may explain the observed beneficial action of combination therapy seen in patient studies in vivo. This may allow a scientific basis to explore future drug interactions that may be helpful in patients, particularly those patients whose disease tends to be severe and may be unresponsive to standard therapies for COPD and/or where high dose ICS have little beneficial clinical effect and have led to side-effects.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||31 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||GR Activity in Induced Sputum Macrophages, and a Change in Inflammatory Biomarkers 2-hours After a Single Dose of Either Symbicort®/Budesonide/Formoterol or in Chronic Obstructive Pulmonary Disease (COPD)|
|Study Start Date :||January 2013|
|Actual Primary Completion Date :||December 2014|
|Actual Study Completion Date :||April 2015|
Experimental: Symbicort®, Formoterol, Budesonide
All Patients will receive randomly one-off dose of the following treatments:
Drug: Symbicort®, Formoterol, Budesonide
Formeterol is Long acting beta 2-agonist (LABA) whereas Budesonide is inhaled corticosteroids (ICS).Patients will randomly receive one-off dose-administration of inhaled treatment (each medication will be taken as two puffs, all via a dry-powder inhaler device = Turbuhaler® to achieve the TOTAL doses).
Other Name: Symbicort® is combination of formoterol and budesonide.
- GR-GRE binding [ Time Frame: 2 hours post inhalation of treatment ]To investigate whether treatment with a single inhaled dose of Symbicort ®-800 or Symbicort ®-400 (a combination of a LABA - formoterol and an ICS - budesonide) will be reflected by changes in GR activation in sputum (on GR-GRE binding in sputum macrophages) that will be equal or superior to a single inhaled clinical dose of ICS alone (at double dose; that is, Pulmicort ®-800 = budesonide).
- IL-6 levels [ Time Frame: 2 hours post inhalation of treatment ]Changes in IL-6 Levels in the sputum supernatant between (i) Symbicort-800 and baseline pre-treatment screening levels (ii) Symbicort-800 and LABA alone (iii) Symbicort-400 and baseline pre-treatment screening levels (iv) Symbicort-400 and LABA alone (v) Symbicort-800 and lower dose Symbicort-400
- CXCL8 levels [ Time Frame: 2 hours post inhalation of treatment ]Changes in CXCL8 concentrations in the sputum supernatant between (i) Symbicort-800 and baseline pre-treatment screening levels (ii) Symbicort-800 and LABA alone (iii) Symbicort-400 and baseline pre-treatment screening levels (iv) Symbicort-400 and LABA alone (v) Symbicort-800 and lower dose Symbicort-400
- Differential cell counts [ Time Frame: 2 hours post inhalation of treatment ]Changes in the cell types (macrophages, neutrophils etc.) obtained from induced sputum between (i) Symbicort-800 and baseline pre-treatment screening levels (ii) Symbicort-800 and LABA alone (iii) Symbicort-400 and baseline pre-treatment screening levels (iv) Symbicort-400 and LABA alone (v) Symbicort-800 and lower dose Symbicort-400
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01787097
|Royal Brompton and Harefield NHS trust|
|London, United Kingdom, SW3 6NP|
|Principal Investigator:||Omar S Usmani, MBBS PhD FHEA FRCP||Imperial College London|