A Pilot Study of the Mechanism of Synergism Between FP and Salmeterol in Preventing COPD Exacerbations

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ClinicalTrials.gov Identifier: NCT00116402

Recruitment Status : Completed

First Posted : June 29, 2005

Last Update Posted : August 5, 2014

Sponsor:

Collaborator:

GlaxoSmithKline

Information provided by (Responsible Party):

University of Chicago

Study Description

Brief Summary:

The purpose of this study is to evaluate the blood and airway of subjects with mild to moderate COPD while undergoing standard treatment.

Condition or disease	Intervention/treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: fluticasone and salmeterol	Phase 1

Detailed Description:

Our objective is to examine the mechanism of the additive/synergistic properties of b2-adrenoceptor stimulation and corticosteroid receptor activation in:

Preventing neutrophil adhesion to specific endothelial ligands, e.g. ICAM-1 and
Undergoing activation as a consequence of this adhesion.

We hypothesize that combination therapy with salmeterol + fluticasone (FP) will:

Augment the inhibition of adhesion of neutrophils obtained from the peripheral blood of study subjects in vitro, by blocking gIV-PLA2 translocation to the nuclear membrane as for eosinophils;
Augment the inhibition of transendothelial migration of neutrophils into airways of subjects with chronic obstructive pulmonary disease;
Augment the numbers and concentrations of pro-inflammatory products in the bronchoalveolar lavage fluid; and
Decrease the number of neutrophils in the bronchial tissue of endobronchial biopsies of treated patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	15 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Pilot Study of the Mechanism of Synergism Between Fluticasone (FP) and Salmeterol in Preventing Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Study Start Date :	January 2005
Actual Primary Completion Date :	September 2009
Actual Study Completion Date :	October 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Drug Information available for: Fluticasone propionate Salmeterol Fluticasone Salmeterol xinafoate Fluticasone furoate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 1 will start with fluticasone 220 mcg BID first and then crossover to combination therapy with salmeterol 50 mcg BID	Drug: fluticasone and salmeterol will start with fluticasone 220 mcg BID first and then crossover to combination therapy with salmeterol 50 mcg BID will start with salmeterol 50 mcg BID first and then crossover to combination therapy with fluticasone 220 mcg BID.
Active Comparator: 2 salmeterol 50 mcg BID then crossover to combination therapy with fluticasone 220 mcg BID	Drug: fluticasone and salmeterol will start with fluticasone 220 mcg BID first and then crossover to combination therapy with salmeterol 50 mcg BID will start with salmeterol 50 mcg BID first and then crossover to combination therapy with fluticasone 220 mcg BID.

Outcome Measures

Primary Outcome Measures :

To evaluate blood and airway neutrophil population in COPD patients by examining adhesion and migration in patients with mild to moderate COPD [ Time Frame: 12 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	50 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Males or females > 50 years of age
Physiologic evidence of COPD defined per ATS guidelines as: cigarette smoking history >20 pack years, FEV1/FVC <70%
Patients must have a post-bronchodilator FEV1 >50% of predicted value at enrollment
Patient must have an O2 saturation measure by pulse oximetry >90% on RA
Must be able to participate in the study, willing to give informed consent, and comply with the study restrictions

Exclusion Criteria:

Women of child-bearing potential defined as females who are less than 5 years post menopausal unless they have had a hysterectomy or bilateral oophorectomy
Observation of any solitary nodule in the lung requiring further medical intervention
Patients on maintenance therapy with oral steroids
Patients with giant bullous disease
Significant other medical conditions, which in the opinion of the investigator, will interfere with the patient's ability to perform the study tests
Presence of a coagulopathy as defined by a platelet count <100,000/mm3, and PT and PTT >1.2 x the upper limit of normal
Concurrent enrollment or participation in any other clinical trials within the past 30 days
Primary diagnosis of asthma
History of alpha 1 antitrypsin deficiency
Any clinically significant and active pulmonary disease that could contribute to dyspnea
Current systemic and inhaled steroids and theophylline

Contacts and Locations

Information from the National Library of Medicine

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): NCT00116402

Locations

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United States, Illinois
Department of Medicine, Pulmonary & Critical Care Section, The University of Chicago
Chicago, Illinois, United States, 60637

Sponsors and Collaborators

University of Chicago

GlaxoSmithKline

Investigators

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Principal Investigator:	Imre Noth, M.D.	University of Chicago

More Information

Publications:

Soriano JB, Kiri VA, Pride NB, Vestbo J. Inhaled corticosteroids with/without long-acting beta-agonists reduce the risk of rehospitalization and death in COPD patients. Am J Respir Med. 2003;2(1):67-74.

Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003 Sep;124(3):834-43.

Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med. 2002 Jun 15;165(12):1592-6.

Kim KP, Rafter JD, Bittova L, Han SK, Snitko Y, Munoz NM, Leff AR, Cho W. Mechanism of human group V phospholipase A2 (PLA2)-induced leukotriene biosynthesis in human neutrophils. A potential role of heparan sulfate binding in PLA2 internalization and degradation. J Biol Chem. 2001 Apr 6;276(14):11126-34. Epub 2000 Dec 15.

Kim YJ, Kim KP, Han SK, Munoz NM, Zhu X, Sano H, Leff AR, Cho W. Group V phospholipase A2 induces leukotriene biosynthesis in human neutrophils through the activation of group IVA phospholipase A2. J Biol Chem. 2002 Sep 27;277(39):36479-88. Epub 2002 Jul 17.

Chang PS, Absood A, Linderman JJ, Omann GM. Magnetic bead isolation of neutrophil plasma membranes and quantification of membrane-associated guanine nucleotide binding proteins. Anal Biochem. 2004 Feb 15;325(2):175-84.

Myou S, Zhu X, Boetticher E, Myo S, Meliton A, Lambertino A, Munoz NM, Leff AR. Blockade of focal clustering and active conformation in beta 2-integrin-mediated adhesion of eosinophils to intercellular adhesion molecule-1 caused by transduction of HIV TAT-dominant negative Ras. J Immunol. 2002 Sep 1;169(5):2670-6.

Reumaux D, de Boer M, Meijer AB, Duthilleul P, Roos D. Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO. J Leukoc Biol. 2003 Jun;73(6):841-9.

Zhu X, Muñoz NM, Kim KP, Sano H, Cho W, Leff AR. Cytosolic phospholipase A2 activation is essential for beta 1 and beta 2 integrin-dependent adhesion of human eosinophils. J Immunol. 1999 Sep 15;163(6):3423-9.

Meliton AY, Muñoz NM, Liu J, Lambertino AT, Boetticher E, Myo S, Myou S, Zhu X, Johnson M, Leff AR. Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils. J Allergy Clin Immunol. 2003 Aug;112(2):404-10.

Reid DW, Ward C, Wang N, Zheng L, Bish R, Orsida B, Walters EH. Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo. Eur Respir J. 2003 Jun;21(6):994-9.

Qiu Y, Zhu J, Bandi V, Atmar RL, Hattotuwa K, Guntupalli KK, Jeffery PK. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003 Oct 15;168(8):968-75. Epub 2003 Jul 11.

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Responsible Party:	University of Chicago
ClinicalTrials.gov Identifier:	NCT00116402 History of Changes
Other Study ID Numbers:	13426B
First Posted:	June 29, 2005 Key Record Dates
Last Update Posted:	August 5, 2014
Last Verified:	August 2014

Keywords provided by University of Chicago:


COPD Chronic Obstructive Pulmonary Disease	Inhaled Corticosteroids Airway Inflammation Bronchoscopy

Additional relevant MeSH terms:

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Lung Diseases Pulmonary Disease, Chronic Obstructive Respiratory Tract Diseases Lung Diseases, Obstructive Fluticasone Salmeterol Xinafoate Anti-Inflammatory Agents Bronchodilator Agents Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs	Anti-Asthmatic Agents Respiratory System Agents Dermatologic Agents Anti-Allergic Agents Adrenergic beta-2 Receptor Agonists Adrenergic beta-Agonists Adrenergic Agonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action

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