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Human Rhinovirus Infection and Airway Remodeling Mediators

Primary Purpose

Asthma

Status
Terminated
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
GMP-grade HRV-39
Bronchoalveolar Lavage
Methacholine Inhalation Challenge
Nasal Lavage
Nasal Scrapings
Bronchial Brushings
Lung Mucosal Biopsy
Allergen Skin Prick Testing
Venipuncture
Bronchoscopy
Spirometry
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Asthma focused on measuring asthma, rhinovirus, remodeling mediators, human rhinovirus infection

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Asthmatics:

  • Male or female volunteers with intermittent or persistent mild to moderate allergic asthma, as defined by GINA guidelines 39.
  • 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.

Sites / Locations

  • University of Calgary

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Asthmatic Group

Healthy Non-Asthmatic Control Group

Arm Description

Subjects with well-controlled, mild-moderate allergic asthma.Subjects will be inoculated with a total dose of 1000 TCID50 of HRV- 39. The inoculum is diluted, as appropriate, in lactated Ringer's solution and delivered via the following procedure: 0.5 ml per nostril is administered by pipette while the subject tilts their head back.

Healthy volunteers. Subjects will be inoculated with a total dose of 1000 TCID50 of HRV- 39. The inoculum is diluted, as appropriate, in lactated Ringer's solution and delivered via the following procedure: 0.5 ml per nostril is administered by pipette while the subject tilts their head back.

Outcomes

Primary Outcome Measures

Bronchial Alveolar Lavage (BAL) Fluid Protein Levels
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
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.
Quantification of inflammatory cells in the lower airways, assessed in BAL fluid and bronchial biopsies.
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.

Full Information

First Posted
May 1, 2013
Last Updated
August 12, 2015
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Asthma and Allergic Diseases Cooperative Research Centers
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1. Study Identification

Unique Protocol Identification Number
NCT01847768
Brief Title
Human Rhinovirus Infection and Airway Remodeling Mediators
Official Title
Comparison of Airway Remodeling Mediators Following Experimental Human Rhinovirus Infection in Subjects With Mild to Moderate Asthma, and in Healthy, Non-asthmatic Control Subjects (AADCRC-UC-01)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Terminated
Why Stopped
Lack of Enrollment
Study Start Date
April 2013 (undefined)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Asthma and Allergic Diseases Cooperative Research Centers

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
In this study, the following subjects will be exposed to human rhinovirus (HRV): those with classification of mild-moderate asthma healthy control subjects. The investigators will 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.
Detailed Description
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 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 goal of this study is 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma
Keywords
asthma, rhinovirus, remodeling mediators, human rhinovirus infection

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Asthmatic Group
Arm Type
Experimental
Arm Description
Subjects with well-controlled, mild-moderate allergic asthma.Subjects will be inoculated with a total dose of 1000 TCID50 of HRV- 39. The inoculum is diluted, as appropriate, in lactated Ringer's solution and delivered via the following procedure: 0.5 ml per nostril is administered by pipette while the subject tilts their head back.
Arm Title
Healthy Non-Asthmatic Control Group
Arm Type
Active Comparator
Arm Description
Healthy volunteers. Subjects will be inoculated with a total dose of 1000 TCID50 of HRV- 39. The inoculum is diluted, as appropriate, in lactated Ringer's solution and delivered via the following procedure: 0.5 ml per nostril is administered by pipette while the subject tilts their head back.
Intervention Type
Biological
Intervention Name(s)
GMP-grade HRV-39
Other Intervention Name(s)
human rhinovirus, common cold
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Bronchoalveolar Lavage
Intervention Type
Drug
Intervention Name(s)
Methacholine Inhalation Challenge
Intervention Description
The purpose of this test is to determine if lung airways narrow by more than 20%, which confirms an asthma diagnosis.
Intervention Type
Procedure
Intervention Name(s)
Nasal Lavage
Intervention Type
Procedure
Intervention Name(s)
Nasal Scrapings
Intervention Description
This process uses a rhinoprobe to gently scrape the mucosal lining of the nose
Intervention Type
Procedure
Intervention Name(s)
Bronchial Brushings
Intervention Type
Procedure
Intervention Name(s)
Lung Mucosal Biopsy
Intervention Type
Procedure
Intervention Name(s)
Allergen Skin Prick Testing
Intervention Description
For the purposes of this study, allergy skin testing will be done with the following aero-allergens: cat epidermis, dog epidermis, horse, grass mix, tree mix, weed mix, ragweed and house dust mite, along with a histamine positive control and a buffer & glycerol negative control.
Intervention Type
Procedure
Intervention Name(s)
Venipuncture
Other Intervention Name(s)
Blood draw
Intervention Description
Peripheral blood for assessment of neutralizing antibodies to HRV-39
Intervention Type
Procedure
Intervention Name(s)
Bronchoscopy
Intervention Description
A small flexible tube the size of a pencil, with a video-camera built into the tip (called a bronchoscope), will be inserted through the nose or mouth and down into the lungs.
Intervention Type
Procedure
Intervention Name(s)
Spirometry
Primary Outcome Measure Information:
Title
Bronchial Alveolar Lavage (BAL) Fluid Protein Levels
Description
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.
Time Frame
Day -7 and Day 4
Secondary Outcome Measure Information:
Title
Quantitative Changes in Gene Expression Between Groups
Description
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.
Time Frame
Day -7 and Day 4
Title
Changes in symptom scores, viral titers, spirometry, airway responsiveness (PC20 methacholine) and FeNO levels.
Time Frame
Day -7 and Day 4
Title
Quantification of inflammatory cells in the lower airways, assessed in BAL fluid and bronchial biopsies.
Time Frame
Day -7 and Day 4
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Asthmatics: Male or female volunteers with intermittent or persistent mild to moderate allergic asthma, as defined by GINA guidelines 39. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Proud, PhD
Organizational Affiliation
University of Calgary
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Calgary
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4Z6
Country
Canada

12. IPD Sharing Statement

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Human Rhinovirus Infection and Airway Remodeling Mediators

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