How Airway Remodeling and Hyperresponsiveness Contribute to Airflow Obstruction in Asthma

This study has been withdrawn prior to enrollment.
(never received funding)
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by:
St. Joseph's Healthcare Hamilton
ClinicalTrials.gov Identifier:
NCT00186693
First received: September 10, 2005
Last updated: July 25, 2011
Last verified: July 2006
  Purpose

Airway hyperresponsiveness is a characteristic feature of the asthma. It is known that there is an association between airway hyperresponsiveness and eosinophilic airway inflammation. However, even though inflammation can be reduced with appropriate asthma therapy, it is typical that airway hyperresponsiveness improves only modestly with treatment. The determinants of airway hyperresponsiveness are unclear.

It is also not clear as to the site of airway narrowing in asthma. It is hypothesized that airways beyond the 4th order have the greatest resistance.

We hope to determine the relationships between the airway inflammation, remodeling of the airway and airway hyperresponsiveness. Through local instillation of methacholine at bronchoscopy we will be able to study proximal and distal airways and the extent to which they constrict in vivo


Condition
Asthma

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: How Airway Remodeling and Hyperresponsiveness Contribute to Airflow Obstruction in Asthma

Resource links provided by NLM:


Further study details as provided by St. Joseph's Healthcare Hamilton:

Estimated Enrollment: 12
Study Start Date: September 2006
Estimated Study Completion Date: June 2009
Detailed Description:

Airway hyperresponsiveness (AHR) is a characteristic feature of the asthmatic condition in humans. There is an association between AHR and eosinophilic airway inflammation. However, even though eosinophilic inflammation can be abolished with appropriate therapy, it is typical that AHR improves only modestly with treatment. The determinants of AHR are poorly understood. Recent data implicate mediators such as the cytokine Interleukin-13 (IL-13), structural changes to the airway wall (remodeling), increased contractility of airway smooth muscle cells (ASMC) and loss of mechanical connections or tethering, as potential factors contributing to AHR.

There is also uncertainty around the site of airway narrowing in asthma. In normal airways, bronchii around the 4th order have the greatest contribution to total resistance. It is hypothesized that the site of greatest resistance is moved distally in asthma and might even involve quite small airways close to the level of terminal bronchioles. Non-invasive methods to assess airway caliber in vivo are still unproven. One untested concern is that the airways of subjects with severe AHR have the potential to close completely putting them at risk of severe and even fatal airflow obstruction.

We propose to study AHR in humans with asthma: we will determine the relationships between AHR and (i) eosinophilic inflammation in the airway (sputum cellularity) via sputum induction, (ii) soluble mediators of inflammation (IL-13, IL-4, IL-5), (iii) remodeling of the airway wall (sub-epithelial fibrosis, ASMC accumulation)via biopsy. In addition we will compare measurements of AHR assessed by inhalation challenge with the results of direct, local installation of methacholine. At bronchoscopy, methacholine is delivered to the airway and bronchoconstriction is assessed directly. This method will allow study of proximal and distal airways, identification of heterogeneity of responses among airways and the extent to which human airways can constrict in vivo.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

adults with asthma

Criteria

Inclusion/ Exclusion Criteria:

  • adults age 18 - 65 years
  • stable asthma, defined as no need for new medical intervention in previous 4 weeks
  • pre FEV1 > or = to 70% and able to have a methacholine challenge
  • hyper-responsiveness as measured by methacholine challenge PC20 < or = 16 mg/ml
  • steroid naive or stable inhaled corticosteroid medication in previous 8 weeks
  • symptomatic treatment with bronchodilators permitted
  • able to give written informed consent
  • no other active/unstable medical conditions as judged by investigator
  • subjects must be suitable for bronchoscopy in opinion of the investigator
  • female subjects must no be pregnant, nursing or unwilling to use appropriate contraception
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00186693

Locations
Canada, Ontario
St Joseph's Healthcare
Hamilton, Ontario, Canada, L8N 4A6
Sponsors and Collaborators
St. Joseph's Healthcare Hamilton
GlaxoSmithKline
Investigators
Principal Investigator: Gerard Cox, MB FRCPC FRCPI McMaster University
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00186693     History of Changes
Other Study ID Numbers: 05-2453
Study First Received: September 10, 2005
Last Updated: July 25, 2011
Health Authority: Canada: Health Canada

Keywords provided by St. Joseph's Healthcare Hamilton:
Airway remodeling
Asthma
Hyper-responsiveness

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 September 15, 2014