Effect of Sitaxsentan on Airway Remodeling in Severe Asthma Clinical Trial
— SitaxOfficial title:
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.
| Status | Terminated |
| Enrollment | 17 |
| Est. completion date | December 2010 |
| Est. primary completion date | December 2010 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 75 Years |
| Eligibility |
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 |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| France | Clinical Investigation center 07, Hopital Bichat | Paris |
| Lead Sponsor | Collaborator |
|---|---|
| Institut National de la Santé Et de la Recherche Médicale, France |
France,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | No | |
| Secondary | 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 | No |