Effect of Symbicort ® on GR in Sputum in COPD

NCT01787097 | Completed Phase 4 Results

• 2 other identifiers: D589BC000042010-020440-35
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Obstructive Lung Disease

Keywords

Chronic Obstructive Lung Disease

Outcome Measures

Primary Outcomes (1)

• GR-GRE Binding (Relative to Baseline)

  Enzyme immunosorbent assay system

  Screening visit and 2 hours post inhalation of treatment

Secondary Outcomes (4)

• Changes in IL-6 Levels

  Screening visit and 2 hours post inhalation of treatment

• Changes in CXCL8 Levels

  Screening visit and 2 hours post inhalation of treatment

• Changes in TNF Alpha

  Screening visit and 2 hours post inhalation of treatment

• Changes in Lung Function Parameter FEV1

  Baseline and 2 hours post inhalation

Study Arms (4)

COPD

ACTIVE COMPARATOR

Participants with COPD

Drug: Formoterol 24ug

Symbicort® total dose 400ug/12ug

ACTIVE COMPARATOR

Symbicort® total dose 400ug/12ug: is a combination of FORM (6ug) and ICS (Budesonide, (BUD) 200ug)

Drug: Symbicort® total dose 400ug/12ug

Symbicort® total dose 800ug/24ug

ACTIVE COMPARATOR

Symbicort® total dose 800ug/24ug: is a combination FORM (12ug) and BUD (400ug) at a higher-dose

Drug: Symbicort® total dose 800ug/24ug

BUD total dose 800ug

ACTIVE COMPARATOR

BUD total dose 800ug: is an intermediate dose of ICS

Drug: BUD total dose 800ug

Interventions

Symbicort® total dose 400ug/12ug DRUG

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

Symbicort® total dose 400ug/12ug

Symbicort® total dose 800ug/24ug DRUG

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

Symbicort® total dose 800ug/24ug

Formoterol 24ug DRUG

Turbuhaler

COPD

BUD total dose 800ug DRUG

Turbuhaler

BUD total dose 800ug

Eligibility Criteria

• Age: 35 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Imperial College London: lead
• AstraZeneca: collaborator

Study Sites (1)

Royal Brompton and Harefield NHS trust

London, SW3 6NP, United Kingdom

Location

Related Publications (6)

• 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.

  PMID: 10958685 BACKGROUND

• 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.

  PMID: 9032192 BACKGROUND

• 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.

  PMID: 10556133 BACKGROUND

• 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.

  PMID: 12583942 BACKGROUND

• 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.

  PMID: 14680078 BACKGROUND

• 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.

  PMID: 21903370 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Formoterol Fumarate

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Results Point of Contact

• Title: Dr Omar S Usmani
• Organization: Imperial College

o.usmani@imperial.ac.uk

+44 (0)20 7351 8051

Study Officials

• Omar S Usmani, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2013
• First Posted: February 8, 2013
• Study Start: January 1, 2013
• Primary Completion: December 1, 2014
• Study Completion: April 1, 2015
• Last Updated: November 23, 2020
• Results First Posted: November 23, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)