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Open Access Study protocol

Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast

Neil C Barnes1*, Marina Saetta2 and Klaus F Rabe3

Author Affiliations

1 GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK and Barts and The London School of Medicine and Dentistry, London, UK

2 Department of Cardiological, Thoracic and Vascular Sciences, Respiratory Disease Clinics,, University of Padova, Via Giustiniani 3, 35128 Padova, Italy

3 Department of Medicine, Kiel, Germany and LungenClinic Grosshansdorf, Grosshansdorf, Germany, members of the German Center for Lung Research, University Kiel, Kiel, Germany

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BMC Pulmonary Medicine 2014, 14:9  doi:10.1186/1471-2466-14-9

Published: 31 January 2014

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators, but above all, CD8+ T-lymphocytes, macrophages and neutrophils are important players in disease pathogenesis. Roflumilast, a first-in-class, potent and selective phosphodiesterase 4 (PDE4) inhibitor, reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and mediators in induced sputum, a surrogate of airway inflammation. However, these anti-inflammatory effects are yet to be confirmed in another robust study directly assessing inflammatory markers in bronchial sub-mucosa.

Methods/Design

An international, 16-week, randomized, double-blind, placebo-controlled, parallel-group study investigating the effects of roflumilast 500 μg once-daily versus placebo on inflammatory parameters in bronchial biopsy tissue specimens, sputum and blood serum. One hundred and fifty patients with COPD and chronic bronchitis for at least 12 months will be recruited into the study and randomized in a 1:1 ratio to receive either roflumilast or placebo. The primary endpoint will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) and the key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed by indirect immunohistochemistry.

Discussion

It is hypothesized that treatment with roflumilast reduces the characteristic inflammation found in the airways of patients with moderate-to-severe COPD, compared with placebo. The design of the present study has built on the work of previous bronchial biopsy studies available in the literature. It is hoped that it will reveal the cellular mechanisms underlying the anti-inflammatory effects of roflumilast and identify potentially important biomarkers and other surrogate endpoints in patients with COPD. The design and rationale for this trial are described herein.

Trial registration

Clinical trial identifier: NCT01509677 (clinicaltrials.gov)

Keywords:
Chronic obstructive pulmonary disease; Roflumilast; Inflammation; Exacerbation; Bronchoscopy; Bronchial biopsy; Protocol; Sputum; Histology