Clinical Trial: Study on the Effects of Sitaxsentan on Airway Remodeling in Patients With Severe Asthma

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Effect of a Receptor Antagonist of Endothelin 1 (Sitaxsentan, Thelin) on Bronchial Remodeling in Severe Asthma With Fixed Bronchial Obstruction

Brief Summary:

Introduction. Despite adequate steroid therapy, a subpopulation of approximately 10% of asthmatics develops severe persistent airflow obstruction. It is now widely agreed that the latter is the consequence of a remodeling process of the airways, characterized by an increase in airway smooth muscle mass, mucus gland hypertrophy, increased thickness of the subepithelial basement membrane, extracellular matrix protein deposition, angiogenesis, fibroblast and myofibroblast accumulation. These phenomena are responsible for airway wall thickening and for decreased airway caliber leading to persistent airflow obstruction.

Endothelin-1 (ET-1) is a small peptide, synthesized in the lung by airway epithelial and smooth muscle cells, as well as inflammatory cells. ET-1 induces bronchoconstriction, mediates eosinophils recruitment during allergic inflammation and contributes to airway remodeling by inducing fibroblasts and smooth muscle cells differentiation and proliferation. In a recent work from Inserm Unit 700, it has been shown that ET-1 was overexpressed in epithelial cells from severe asthmatic patients as compared to patients with less severe disease, and that ET-1 expression was strongly correlated with airway obstruction (measured by FEV1) and on bronchial biopsies with airway smooth muscle areas. In another study, we have shown that a polymorphism of the receptor for ET-1 was strongly associated with the degree of airway obstruction in a population of asthmatic patients. All these data suggest that inhibition of the ET-1 pathway could be a potential therapeutic option in patients with steroids refractory asthma and irreversible airway obstruction. Bosentan, a specific inhibitor of ET-1 receptors which is actually used in patients with pulmonary hypertension, improves survival and inhibits vascular remodeling.

Aim and strate

Detailed Summary:
Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Current Primary Outcome: Changes in airway remodeling analyzed on bronchial biopsy specimens at inclusion and after one year by immunohistochemistry and morphometry (smooth muscle area, and submucosal fibroblasts count). [ Time Frame: 2 years ]

Original Primary Outcome: Same as current

Current Secondary Outcome: FEV1,clinical status, asthma exacerbations, steroids use, need for emergency care, asthma symptoms and quality of life,exhaled NO and induced sputum cytology. [ Time Frame: 2 years ]

Original Secondary Outcome: Same as current

Information By: Institut National de la Santé Et de la Recherche Médicale, France

Dates:
Date Received: January 14, 2010
Date Started: November 2009
Date Completion:
Last Updated: May 9, 2012
Last Verified: May 2012