Study on the Effects of Sitaxsentan on Airway Remodeling in Patients With Severe Asthma (Sitax)

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

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 strategy. To study the impact on airway remodeling and clinical status of an antagonist of the endothelin receptors (Sitaxentan 100mg/day) over a 12-month period, in a prospective randomised placebo-controlled trial involving two parallel groups of 25 severe asthmatic patients with irreversible airflow obstruction (FEV1≤ 70% of predicted) . Various hallmarks of airway remodeling will be analyzed on bronchial biopsy specimens by immunohistochemistry and morphometry. These findings will be correlated with the results of pulmonary function tests. Twenty-five patients will be included in each group. Remodeling will be measured on bronchial biopsies performed during fiberoptic bronchoscopy at inclusion and after one year, by assessing smooth muscle area, submucosal fibroblasts count and basement membrane thickness. Every 3 months, bronchial obstruction (FEV1), clinical status, asthma exacerbations, steroids use, need for emergency care, asthma symptoms and quality of life will be assessed. Evaluation of airway inflammation will be assessed every 3 months by exhaled NO and induced sputum cytology.

This proof of concept study will validate ET-1 as a new molecular target for treating airway remodeling in patients with severe asthma.

Study Overview

• Status: Terminated
• Conditions: Effect of Sitaxsentan on Airway Remodeling in Severe Asthma
• Intervention / Treatment: Drug: sitaxentan; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75018
    • Clinical Investigation center 07, Hopital Bichat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 50 non smoking (25 on active treatment and 25 on placebo) patients with severe asthmatic patients (age over 18 and less than 70) and irreversible airflow obstruction (FEV1≤ 70% of predicted)

Exclusion Criteria:

• Abnormal liver chemistry at inclusion, female without acceptable contraceptive methods

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: sitaxsentan, airway remodeling; Blinded, randomised placebo-controlled trial involving two parallel groups of severe asthmatic patients with irreversible airflow obstruction (FEV1≤ 70% of predicted) .	Drug: sitaxentan; 100 mg once a day during one year. Bronchial fibroscopy; Drug: placebo; placebo, one per day, during one year. Bronchial fibroscopy
Placebo Comparator: placebo, airway remodeling; Blinded, randomised placebo-controlled trial involving two parallel groups of severe asthmatic patients with irreversible airflow obstruction (FEV1≤ 70% of predicted) .	Drug: placebo; placebo, one per day, during one year. Bronchial fibroscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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).	2 years

Secondary Outcome Measures

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: January 14, 2010
• First Submitted That Met QC Criteria: January 14, 2010
• First Posted (Estimate): January 15, 2010

Study Record Updates

• Last Update Posted (Estimate): May 10, 2012
• Last Update Submitted That Met QC Criteria: May 9, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: asthma; airway remodeling; airway obstruction
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Airway Remodeling; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Sitaxsentan
• Other Study ID Numbers: C07-25

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No