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

Barnes NC, Saetta M, Rabe KF - BMC Pulm Med (2014)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK and Barts and The London School of Medicine and Dentistry, London, UK. neil.c.barnes@gsk.com.

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.

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Schematic design of the clinical study.
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Figure 1: Schematic design of the clinical study.

Mentions: An international, 16-week, randomized, double-blind, placebo-controlled, parallel group study (Figure 1) investigating the effect of roflumilast 500 μg once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimens, sputum and blood serum (clinical trial identifier: NCT01509677). Patients will be equally randomized to either roflumilast treatment or placebo in a 1:1 ratio by means of a computerized central randomization system IVRS/IWRS. The system will assign one or two appropriate trial treatment kit(s) from the stock available at the site for each patient. The primary endpoint of the study will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) evaluated from randomization to the end of the intervention period. The key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed over the same timeframe, but a host of other secondary outcomes will also be assessed (Table 1). The study will be conducted at 11 European sites specializing in lung diseases.


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

Barnes NC, Saetta M, Rabe KF - BMC Pulm Med (2014)

Schematic design of the clinical study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927659&req=5

Figure 1: Schematic design of the clinical study.
Mentions: An international, 16-week, randomized, double-blind, placebo-controlled, parallel group study (Figure 1) investigating the effect of roflumilast 500 μg once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimens, sputum and blood serum (clinical trial identifier: NCT01509677). Patients will be equally randomized to either roflumilast treatment or placebo in a 1:1 ratio by means of a computerized central randomization system IVRS/IWRS. The system will assign one or two appropriate trial treatment kit(s) from the stock available at the site for each patient. The primary endpoint of the study will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) evaluated from randomization to the end of the intervention period. The key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed over the same timeframe, but a host of other secondary outcomes will also be assessed (Table 1). The study will be conducted at 11 European sites specializing in lung diseases.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK and Barts and The London School of Medicine and Dentistry, London, UK. neil.c.barnes@gsk.com.

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.

Show MeSH
Related in: MedlinePlus