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Chronic Obstructive Lung DiseasePhase 4NCT01787097

Effect of Symbicort ® on GR in Sputum in COPD

A Phase 4 study testing Symbicort® total dose 400ug/12ug, Symbicort® total dose 800ug/24ug and Formoterol 24ug in people with Chronic Obstructive Lung Disease, run by Imperial College London at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 35 to 80 years
Conditions the study is for
Chronic Obstructive Lung Disease
What is being tested?
Symbicort® total dose 400ug/12ug, Symbicort® total dose 800ug/24ug and Formoterol 24ug
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
1 siteUnited Kingdom
Study dates
Jan 2013to Apr 2015
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 35 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients (n=30) 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).
  • Aged 38-80 years inclusive
  • FEV1 <15% reversibility (not % predicted) and/or an increase of <200 ml after inhaled β2-agonists (400 μg salbutamol)
  • 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.
  • 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.
  • Capable of giving informed consent.

Who cannot join

  • As a result of the medical interview, physical examination or screening investigations, the Physician Responsible considers the volunteer unfit for the study.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
Show all 10Show fewer
  • 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).
  • Patients who have a history of drug allergy which, in the opinion of the Unit Physician, contraindicates his/her participation in the study.
  • 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).
  • 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).

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • Royal Brompton and Harefield NHS trust

    London, SW3 6NP

Other trials in United Kingdom

About this study

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)

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.

Read the 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.

Being tested
Symbicort® total dose 400ug/12ug, Symbicort® total dose 800ug/24ug, Formoterol 24ug, BUD total dose 800ug
Keywords
Chronic Obstructive Lung Disease
Medical subject headings
Pulmonary Disease, Chronic Obstructive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Symbicort® total dose 400ug/12ugDrug

    Symbicort® is combination of formoterol 400ug and budesonide 12ug. Single dose

  • Symbicort® total dose 800ug/24ugDrug

    Symbicort® is combination of formoterol 800ug and budesonide 24ug. Single dose

  • Formoterol 24ugDrug

    Turbuhaler

  • BUD total dose 800ugDrug

    Turbuhaler

Study groups in NCT01787097
Study groupRoleWhat they receive
COPDActive comparatorParticipants with COPD
Receives: Drug: Formoterol 24ug
Symbicort® total dose 400ug/12ugActive comparatorSymbicort® total dose 400ug/12ug: is a combination of FORM (6ug) and ICS (Budesonide, (BUD) 200ug)
Receives: Drug: Symbicort® total dose 400ug/12ug
Symbicort® total dose 800ug/24ugActive comparatorSymbicort® total dose 800ug/24ug: is a combination FORM (12ug) and BUD (400ug) at a higher-dose
Receives: Drug: Symbicort® total dose 800ug/24ug
BUD total dose 800ugActive comparatorBUD total dose 800ug: is an intermediate dose of ICS
Receives: Drug: BUD total dose 800ug

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. GR-GRE Binding (Relative to Baseline)

    Enzyme immunosorbent assay system

    Measured: Screening visit and 2 hours post inhalation of treatment

Secondary outcomes (4)
  1. Changes in IL-6 Levels

    Changes in IL-6 Levels in the sputum supernatant compared to screening visit

    Measured: Screening visit and 2 hours post inhalation of treatment

  2. Changes in CXCL8 Levels

    Changes in CXCL8 concentrations in sputum compared to screening visit.

    Measured: Screening visit and 2 hours post inhalation of treatment

  3. Changes in TNF Alpha

    Sputum TNF-alpha levels obtained from induced sputum compared to screening visit.

    Measured: Screening visit and 2 hours post inhalation of treatment

  4. Changes in Lung Function Parameter FEV1

    Improvement in FEV1 compared to baseline levels.

    Measured: Baseline and 2 hours post inhalation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Feb 2013 (estimated)
  2. Study startJan 2013
  3. Primary completionDec 2014
  4. Study completionApr 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01787097
Sponsor's protocol ID
D589BC00004
Other IDs
2010-020440-35
Status last verified
Oct 2020
First submitted
4 Feb 2013
Last updated
23 Nov 2020
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. 2000 Sep;20(18):6891-903. doi: 10.1128/MCB.20.18.6891-6903.2000.

    PubMed 10958685
  • Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med. 1997 Feb;155(2):542-8. doi: 10.1164/ajrccm.155.2.9032192.

    PubMed 9032192
  • Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1635-9. doi: 10.1164/ajrccm.160.5.9811058.

    PubMed 10556133
  • Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C; TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003 Feb 8;361(9356):449-56. doi: 10.1016/S0140-6736(03)12459-2.

    PubMed 12583942
  • Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003 Dec;22(6):912-9. doi: 10.1183/09031936.03.00027003.

    PubMed 14680078
  • 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.

    PubMed 21903370

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Symbicort® total dose 400ug/12ug, Symbicort® total dose 800ug/24ug and Formoterol 24ug in people with Chronic Obstructive Lung Disease, run by Imperial College London at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

GR-GRE Binding (Relative to Baseline) (time frame: Screening visit and 2 hours post inhalation of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01787097, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Nov 2020.

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