Comparison of Airway Remodeling Mediators Following Experimental Human Rhinovirus Infection in Subjects With Mild to Moderate Asthma and in Healthy, Non-asthmatic Control Subjects.

This study is currently recruiting participants.
Verified April 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01847768
First received: May 1, 2013
Last updated: April 10, 2014
Last verified: April 2014
  Purpose

Although changes in the lungs, known as remodeling, are a feature of asthma, the causes and mechanisms involved in the process have not yet been found. Recently, it has been established that remodeling can be observed in children prior to a formal diagnosis of asthma. Clinical studies indicate that human rhinovirus (HRV) "common cold" infections are a common cause of recurrent respiratory illnesses in childhood, and children with HRV-associated wheezing episodes have an increased risk of developing asthma. This led to the hypothesis that HRV infections may play a central role in the start of the airway remodeling leading to asthma.

The investigators plan to perform a study in which the investigators will expose subjects with mild-moderate asthma and healthy control subjects to HRV. This will allow us to accurately study the kinetics of HRV-induced inflammatory and remodeling responses in a well characterized group of asthmatic subjects and compare these outcomes to those in a healthy, non-asthmatic control group. The investigators will try to determine if alterations in relevant airway remodeling growth factors differ between healthy controls and asthmatic subjects, pre- and post-HRV infection. These growth factors will be assessed in bronchoalveolar lavage (BAL) fluid and endobronchial biopsy tissues and correlated with viral levels in both nasal lavage and BAL fluid.


Condition Intervention
Asthma
Biological: GMP-grade HRV-39

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Bronchial Alveolar Lavage (BAL) Fluid Protein Levels [ Time Frame: Day -7 and Day 4 ] [ Designated as safety issue: No ]
    The primary endpoint will be the protein levels in BAL fluid at Day 4 (post-infection) minus the value at Day -7 (pre-infection) for each of MMP-9, VEGF amphiregulin and activin A.


Secondary Outcome Measures:
  • Quantitative Changes in Gene Expression Between Groups [ Time Frame: Day -7 and Day 4 ] [ Designated as safety issue: No ]
    Quantitative changes in gene expression between groups in BAL fluid, bronchial brushings, nasal scrapings and mucosal biopsies, for selected airway remodeling mediator genes, including MMP-9, amphiregulin, VEGF and activin A.

  • Changes in symptom scores, viral titers, spirometry, airway responsiveness (PC20 methacholine) and FeNO levels. [ Time Frame: Day -7 and Day 4 ] [ Designated as safety issue: No ]
  • Quantification of inflammatory cells in the lower airways, assessed in BAL fluid and bronchial biopsies. [ Time Frame: Day -7 and Day 4 ] [ Designated as safety issue: No ]
  • Correlation of gene expression and protein levels of selected mediators with viral titer, symptom scores and numbers of inflammatory cells in the upper and lower airways. [ Time Frame: Day -7 and Day 4 ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: April 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Asthmatics
subjects with well-controlled, mild-moderate asthma
Biological: GMP-grade HRV-39
Experimental rhinovirus infection: an FDA approved, GMP-grade HRV-39 stock (gift from Dr. Ronald B. Turner, University of Virginia), which has now been approved by Health Canada for human experimental use, will be used in this study.
Other Names:
  • human rhinovirus
  • common cold
Active Comparator: Non-asthmatics Biological: GMP-grade HRV-39
Experimental rhinovirus infection: an FDA approved, GMP-grade HRV-39 stock (gift from Dr. Ronald B. Turner, University of Virginia), which has now been approved by Health Canada for human experimental use, will be used in this study.
Other Names:
  • human rhinovirus
  • common cold

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Asthmatics:

  • Male or female volunteers with intermittent or persistent mild to moderate allergic asthma, as defined by GINA guidelines39.
  • Between ≥18 and ≤ 50 years of age.
  • Objective evidence of variable airflow limitation (≥12% and at least 200mL post-bronchodilator reversibility from baseline), or airway hyperresponsiveness (PC20 methacholine <16mg/ml) at the screening visit or within past 24 months.
  • Pre-bronchodilator spirometry at baseline; FEV1 ≥70% of predicted; FEV1/VC ≥50%.
  • Atopic, as evidenced by positive skin prick tests to ≥1 common aero-allergen, where positive is defined by a wheal of ≥2 mm compared to the negative control.
  • Not be exposed to sensitizing seasonal allergens for at least 4 weeks before the study. Chronic exposure to perennial allergens will be permitted.
  • Asthma symptoms controlled by either inhaled β22-agonists alone, or by low or moderate dose ICS (≤800mcg of budesonide or equivalent per day), administered either as monotherapy or in a fixed-dose combination with a long-acting β22-agonist (LABA). The doses of these maintenance medications should have remained stable for the 4 weeks prior to the study screening phase (Visit 2).
  • Stable asthma symptoms, with no history of asthma exacerbation requiring short burst prednisone treatment within the 3 months prior to study entry.
  • Be a non-smoker, as defined as no smoking in past 12 months, and have a lifetime ≤ 10 pack-year smoking history.
  • In good general health (other than asthma) without clinically significant medical history of other co-morbidities, and a BMI of ≤ 30 kg/m2.
  • Have no history of any life threatening episode of asthma, as judged by the study physician; this may include, but not be limited to, prior ICU admission or intubation.
  • Subjects, or their partners, must be using a reliable form of contraception continuously from 4 weeks prior, to 4 weeks post participation.

Non-Asthmatics:

  • Male or female volunteers, ≥18 and ≤ 50 years of age, in good general health, without a clinically significant medical history and a BMI of ≤ 30 kg/m2.
  • Non-asthmatic, as defined by history and normal spirometry (FEV1 ≥80% and FEV1/FVC ≥75% of predicted value).
  • Normal airway responsiveness (PC20 methacholine ≥16 mg/ml)
  • Non-atopic, as determined by skin prick tests to common aero-allergens, where positive test defined as a wheal of ≥ 2 mm compared to the negative control.
  • Be a non-smoker for ≥1 year, and have a lifetime ≤ 10 pack-year smoking history of smoking.
  • Subjects, or their partners, must be using a reliable form of contraception continuously from 4 weeks prior, to 4 weeks post participation.
  • All potentially eligible study subjects must be willing to participate in study, and be able to provide written consent prior to starting the study. The study protocol and consent form will be approved by the Calgary Conjoint Health Research Ethics Board.

Exclusion Criteria:

  • Presence of neutralizing antibodies to HRV-39 at the screening visit to a titer of ≥ 1:2.
  • Have symptoms of an active viral respiratory tract infection (cold symptoms), corroborated by a score of 3 or higher on the Jackson cold symptom questionnaire, during the screening phase (Visit 3).
  • Current pregnancy or positive urine pregnancy test at screening or during the study.
  • Use of any of the following medications in preceding 4 weeks prior to study entry and during the study: : oral and topical antihistamines, leukotriene receptor antagonists, inhaled anticholinergics, non-steroidal anti-inflammatory drugs (NSAIDS), antibiotics and anti-viral medications, over the counter 'cold' and influenza remedies, including decongestants, and oral anticoagulants.
  • Use of prednisone within the last 3 months.
  • Current acute or chronic illness (including infection) or recent recovery (within 4 weeks) from acute illness which could, in the opinion of the study physician, alter inflammatory responses (e.g., influenza, cold or other respiratory infection, etc.). • Autoimmune disease or immunodeficiency, or any household contacts who are known to be immune deficient.
  • Known allergy to lidocaine
  • Any other significant concomitant medical issue, or findings on physical examination or laboratory testing that, in the opinion of the study physician, may pose additional risks from participation in the study (including undergoing bronchoscopy), or which may impact the quality or interpretation of the data obtained from the study.
  • Clinically significant pre-bronchoscopy safety assessment laboratory tests (CBC, INR, electrolytes and creatinine), as well as a positive urine pregnancy test on all female subjects of child-bearing age, will be done at visit 2 (day -26) and visit 5 (Day 0) prior to bronchoscopy on Day -7 and Day 4.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01847768

Locations
Canada, Alberta
University of Calgary Recruiting
Calgary, Alberta, Canada, T2N 4Z6
Contact: Curtis Dumonceaux, BSc, RRT, RCPTC(P), CCRP    403-220-2123    cjdumonc@ucalgary.ca   
Principal Investigator: David Proud, MD         
Sub-Investigator: Richard Leigh, MD         
Sponsors and Collaborators
Investigators
Principal Investigator: David Proud, PhD University of Calgary
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01847768     History of Changes
Other Study ID Numbers: DAIT AADCRC-UC-01
Study First Received: May 1, 2013
Last Updated: April 10, 2014
Health Authority: United States: Federal Government

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