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

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Pilot Study of the Mechanism of Synergism Between Fluticasone (FP) and Salmeterol in Preventing Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00116402
• Other study ID #: 13426B
• Status: Completed
• Phase: Phase 1
• First received: June 28, 2005
• Last updated: August 4, 2014
• Start date: January 2005
• Est. completion date: October 2009

Study information

• Verified date: August 2014
• Source: University of Chicago
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: October 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

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.

Locations

Country	Name	City	State
United States	Department of Medicine, Pulmonary & Critical Care Section, The University of Chicago	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
University of Chicago	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate blood and airway neutrophil population in COPD patients by examining adhesion and migration in patients with mild to moderate COPD		12 weeks	No