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Human Rhinovirus Infection and Airway Remodeling Mediators

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ClinicalTrials.gov Identifier: NCT01847768
Recruitment Status : Terminated (Lack of Enrollment)
First Posted : May 7, 2013
Last Update Posted : August 14, 2015
Sponsor:
Collaborator:
Asthma and Allergic Diseases Cooperative Research Centers
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

May 1, 2013
May 7, 2013
August 14, 2015
April 2013
July 2015   (Final data collection date for primary outcome measure)
Bronchial Alveolar Lavage (BAL) Fluid Protein Levels [ Time Frame: Day -7 and Day 4 ]
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.
Same as current
Complete list of historical versions of study NCT01847768 on ClinicalTrials.gov Archive Site
  • Quantitative Changes in Gene Expression Between Groups [ Time Frame: Day -7 and Day 4 ]
    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 ]
  • Quantification of inflammatory cells in the lower airways, assessed in BAL fluid and bronchial biopsies. [ Time Frame: Day -7 and Day 4 ]
  • 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 ]
Same as current
Not Provided
Not Provided
 
Human Rhinovirus Infection and Airway Remodeling Mediators
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)

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.

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.

Interventional
Not Applicable
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
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
  • Procedure: Bronchoalveolar Lavage
  • Drug: Methacholine Inhalation Challenge
    The purpose of this test is to determine if lung airways narrow by more than 20%, which confirms an asthma diagnosis.
  • Procedure: Nasal Lavage
  • Procedure: Nasal Scrapings
    This process uses a rhinoprobe to gently scrape the mucosal lining of the nose
  • Procedure: Bronchial Brushings
  • Procedure: Lung Mucosal Biopsy
  • Procedure: Allergen Skin Prick Testing
    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.
  • Procedure: Venipuncture
    Peripheral blood for assessment of neutralizing antibodies to HRV-39
    Other Name: Blood draw
  • Procedure: Bronchoscopy
    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.
  • Procedure: Spirometry
  • Experimental: Asthmatic Group

    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.

    Interventions:
    • Biological: GMP-grade HRV-39
    • Procedure: Bronchoalveolar Lavage
    • Drug: Methacholine Inhalation Challenge
    • Procedure: Nasal Lavage
    • Procedure: Nasal Scrapings
    • Procedure: Bronchial Brushings
    • Procedure: Lung Mucosal Biopsy
    • Procedure: Allergen Skin Prick Testing
    • Procedure: Venipuncture
    • Procedure: Bronchoscopy
    • Procedure: Spirometry
  • Active Comparator: Healthy Non-Asthmatic Control Group

    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.

    Interventions:
    • Biological: GMP-grade HRV-39
    • Procedure: Bronchoalveolar Lavage
    • Drug: Methacholine Inhalation Challenge
    • Procedure: Nasal Lavage
    • Procedure: Nasal Scrapings
    • Procedure: Bronchial Brushings
    • Procedure: Lung Mucosal Biopsy
    • Procedure: Allergen Skin Prick Testing
    • Procedure: Venipuncture
    • Procedure: Bronchoscopy
    • Procedure: Spirometry
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
2
30
July 2015
July 2015   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 50 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
Canada
 
 
NCT01847768
DAIT AADCRC-UC-01
AADCRC-UC-01 ( Other Identifier: Asthma and Allergic Diseases Cooperative Research Centers )
No
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Asthma and Allergic Diseases Cooperative Research Centers
Principal Investigator: David Proud, PhD University of Calgary
National Institute of Allergy and Infectious Diseases (NIAID)
August 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP