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

This study has been terminated.
(sitaxentan is not commercialized anymore)
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier:
NCT01050491
First received: January 14, 2010
Last updated: May 9, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Effect of Sitaxsentan on Airway Remodeling in Severe Asthma
Drug: sitaxentan
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Effect of a Receptor Antagonist of Endothelin 1 (Sitaxsentan, Thelin) on Bronchial Remodeling in Severe Asthma With Fixed Bronchial Obstruction

Resource links provided by NLM:


Further study details as provided by Institut National de la Santé Et de la Recherche Médicale, France:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 17
Study Start Date: November 2009
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01050491

Locations
France
Clinical Investigation center 07, Hopital Bichat
Paris, France, 75018
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
  More Information

No publications provided

Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT01050491     History of Changes
Other Study ID Numbers: C07-25
Study First Received: January 14, 2010
Last Updated: May 9, 2012
Health Authority: France: National Consultative Ethics Committee for Health and Life Sciences

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
asthma
airway remodeling
airway obstruction

Additional relevant MeSH terms:
Asthma
Airway Remodeling
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Pathological Conditions, Anatomical

ClinicalTrials.gov processed this record on April 17, 2014