Effect of Symbicort ® on GR in Sputum in COPD

Overview[ - collapse ][ - ]

Purpose 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.
ConditionChronic Obstructive Lung Disease
InterventionDrug: Symbicort®, Formoterol, Budesonide
PhasePhase 4
SponsorImperial College London
Responsible PartyImperial College London
ClinicalTrials.gov IdentifierNCT01787097
First ReceivedFebruary 4, 2013
Last UpdatedApril 12, 2013
Last verifiedJanuary 2013

Tracking Information[ + expand ][ + ]

First Received DateFebruary 4, 2013
Last Updated DateApril 12, 2013
Start DateJanuary 2013
Estimated Primary Completion DateDecember 2014
Current Primary Outcome MeasuresGR-GRE binding [Time Frame: 2 hours post inhalation of treatment] [Designated as safety issue: No]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).
Current Secondary Outcome Measures
  • IL-6 levels [Time Frame: 2 hours post inhalation of treatment] [Designated as safety issue: No]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] [Designated as safety issue: No]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] [Designated as safety issue: No]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

Descriptive Information[ + expand ][ + ]

Brief TitleEffect of Symbicort ® on GR in Sputum in COPD
Official TitleGR 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)
Brief Summary
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.
Detailed Description
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 TypeInterventional
Study PhasePhase 4
Study DesignEndpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
ConditionChronic Obstructive Lung Disease
InterventionDrug: 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 Names:
Symbicort® is combination of formoterol and budesonide.
Study Arm (s)Experimental: Symbicort®, Formoterol, Budesonide
All Patients will receive randomly one-off dose of the following treatments:
Formoterol (FORM) total dose 24ug: is a LABA chosen at a higher clinical dose to determine whether this treatment can achieve an effective treatment response on GR in sputum cells compare to treatments 2 and 3.
Symbicort® total dose 400ug/12ug: is a combination of FORM (6ug) and ICS (Budesonide, (BUD) 200ug) at a lower-dose to determine whether this combination can have an effect on GR in sputum cells compare to treatment 4, 1 and 3.
Symbicort® total dose 800ug/24ug: is a combination FORM (12ug) and BUD (400ug) at a higher-dose, chosen to compare the effect on GR with treatment 4 and 1
BUD total dose 800ug: is an intermediate dose of ICS chosen for comparison with treatments 2 and 3 on GR.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment35
Estimated Completion DateDecember 2014
Estimated Primary Completion DateDecember 2014
Eligibility Criteria
Inclusion Criteria:

1. Patients (n=35) with chronic obstructive pulmonary disease (COPD) with
mild-to-moderate disease severity (GOLD 1 and 2 guidelines). The post-bronchodilator
FEV1 will be used in the criteria to define GOLD severity (reference 7/Table 1).

2. Aged 38-80 years inclusive

3. FEV1 <15% reversibility (not % predicted) and/or an increase of <200 ml after inhaled
β2-agonists (400 μg salbutamol)

4. Patients will be allowed to use their current short-acting β2-agonists (SABA) and
long-acting β2-agonists (LABA) and short-acting muscarinic-antagonist (SAMA) and
long-acting muscarinic-antagonists (LAMA). However they should refrain from
short-acting β2-agonists (SABA) and short-acting muscarinic-antagonist (SAMA) for 6
hours before the study visit and for long-acting β2-agonists (LABA) and long-acting
muscarinic-antagonists (LAMA) at least 12 hours before the study visit, unless needed
by the patient's clinical condition.

5. Theophylline (an oral tablet bronchodilator) will be required to be stopped at least
3 days prior to start of Study Visit one, and patients will not be allowed this
treatment during the study as it may affect the GR response and the bronchodilator
(lung function, spirometry) responses.

6. Capable of giving informed consent.

Exclusion Criteria:

1. As a result of the medical interview, physical examination or screening
investigations, the Physician Responsible considers the volunteer unfit for the
study.

2. Patients who have a clinical diagnosis of Asthma, as decided by the Study
Investigators, as this does not fulfil the diagnosis of chronic obstructive pulmonary
disease (COPD).

3. Patients who have had a history of an upper or lower respiratory infection (including
sinusitis) within 4 weeks prior to study entry, as this can affect the breathing
response.

4. Patients who have received oral or parenteral steroids within 4 weeks prior to study
entry, as this can affect the breathing response and signifies that their condition
needs to be controlled better.

5. Patients who have been hospitalised for a COPD exacerbation within 1 month of study
entry and/or has received antibiotics within 4 weeks of study entry, as this
signifies that their condition needs to be controlled better.

6. Patients taking any regular medication that is contraindicated (as indicated in the
British National Formulary) in those about to receive the study medications listed in
this protocol; other than the oral contraceptive pill.

7. Any evidence of a positive pregnancy urine test for female volunteers or females who
are pregnant or lactating or are likely to become pregnant during the trial. Women of
child−bearing potential may be included in the study if, in the opinion of the
investigator, they are taking adequate contraceptive precautions (which will be
directly enquired at the screening visit).

8. Patients who have a history of drug allergy which, in the opinion of the Unit
Physician, contraindicates his/her participation in the study.

9. Patients with a known or suspected allergy to corticosteroids or any component of the
formulations and/or suspected hypersensitivity to inhaled corticosteroid (this will
be asked directly at the screening visit).

10. Patients who regularly, or on average, drink more than 21 units of alcohol (males)
and 14 units of alcohol (female) per week (this will be asked directly at the
screening visit).
GenderBoth
Ages35 Years
Accepts Healthy VolunteersNo
ContactsContact: Omar S Usmani, MBBS, PhD, FHEA, FRCP
+44 (0)20 7351 8051
o.usmani@imperial.ac.uk
Location CountriesUnited Kingdom

Administrative Information[ + expand ][ + ]

NCT Number NCT01787097
Other Study ID NumbersD589BC00004
Has Data Monitoring CommitteeNo
Information Provided ByImperial College London
Study SponsorImperial College London
CollaboratorsAstraZeneca
Investigators Principal Investigator: Omar S Usmani, MBBS PhD FHEA FRCP Imperial College London
Verification DateJanuary 2013

Locations[ + expand ][ + ]

Royal Brompton and Harefield NHS trust
London, United Kingdom, SW3 6NP
Contact: Sally NS Meah, RGN | + 44 (0)2073518051 | sally.meah@imperial.ac.uk
Principal Investigator: Omar S Usmani, MBBS PhD FRCP
Recruiting