Airway Remodeling and Rhinovirus in Asthmatics

NCT05775952 | Recruiting

• 1 other identifier: ARRA
• Study Type: observational
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Human rhinovirus is also called the "common cold virus" because it causes at least half of all of the common colds experienced each year. In patients with asthma, getting a rhinovirus infection can cause worsening of asthma symptoms. Although these symptoms are well known, researchers do not fully understand how the virus worsens these asthma symptoms, nor do they really know whether virus infection causes longer term structural changes (often referred to as airway remodeling) in the airways. This study plans to address and answer these questions. Doing so will provide the researchers with a better understanding of how to treat the worsening of asthma that are caused by human rhinovirus infections. The epithelial cell is the cell that lines the surface of your airways from your nose down to your lungs, and is also the cell type that gets infected by rhinovirus. At present, it is thought that the virus causes symptoms by changing epithelial cell biology in a way that causes airway inflammation. Some of these inflammatory molecules are also thought to cause scarring (remodeling) of the airways, which over time, may lead to a loss of lung function. In order to examine how the virus causes inflammation, many earlier studies have used experimental infection with the virus and have measured various markers of inflammation. The purpose of this study is to compare the levels of inflammatory and remodeling products in the airways of study participants with mild to moderate asthma and healthy, non-asthmatic subjects after infection with rhinovirus (the common cold virus).

Conditions

Asthma; Respiratory Disease

Keywords

Human Rhinovirus

Outcome Measures

Primary Outcomes (3)

• The change between pre- and post-rhinoviral infection.

  Experimental rhinoviral infection will be confirmed by detection of viral shedding in nasal lavage fluids using conventional viral titre assay using MRC-5 fibroblasts, RT-PCR for HRV 39 viral RNA and standard viral titer assays, and/or by a 4-fold increase in HRV-39 neutralizing serum antibody titre 4 weeks after infection.

  Baseline (Visit 1) to Week 8 (Visit 11).

• Change of protein levels.

  Immunohistochemistry will be performed on bronchial biopsies to identify the following cells: total leukocytes (CD45+), T-lymphocytes (CD3+), T-lymphocyte subsets (CD4+ and CD8+), B-lymphocytes (CD20+), neutrophils (anti-neutrophil elastase), macrophages (CD68+), mast cells (anti-tryptase, AA1), myofibroblasts (α-smooth muscle actin) and blood vessels (CD34+).

  Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).

• The change in the lower airway secretions and tissues for selected airway remodeling mediators.

  Airway remodeling mediators including matrix metalloproteinase (MMP)-9, amphiregulin, vascular endothelial growth factor (VEGF) and activin A will be assess from bronchial lavage and biopsy samples.

  Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).

Secondary Outcomes (10)

• Quantitative changes

  Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).

• Number of airway myofibroblasts

  Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).

• Changes in symptom scores - asthma control questionnaire (ACQ)

  Baseline (Visit 1) to Week 8 (Visit 11).

• Changes in cold symptom questionnaire

  Baseline (Visit 1) to Week 8 (Visit 11).

• Changes in viral titres

  Baseline (Visit 1) to Week 8 (Visit 11).

Study Arms (2)

Asthma Cohort

Subjects with well-controlled, mild-moderate asthma (≥12% post-bronchodilator reversibility or PC20 methacholine \<16mg/mL at screening or within past 5 years). Subjects will be inoculated with a total dose of 1000 tissue culture-infective dose 50% (TCID50) of rhinovirus (HRV) 39. The inoculum is diluted as appropriate in lactated Ringer's solution and delivered via a two step procedure: 0.25 ml per nostril is administered by pipette while the subject tilts their head back. It is anticipated that subjects will develop mild to moderate symptoms that are transient (lasting 3-7 days) and typically consist of nasal congestion, throat irritation, malaise and increased mucoid secretions. Subjects will record cold symptoms twice daily, using a diary card listing 8 symptoms, each of which are scored 0 to 3 on a basis of severity. Subjects will only be inoculated with HRV-39 once at Visit 5.

Biological: HRV-39

Healthy, Non-asthmatic Cohort

Healthy non-asthmatic control subjects. Subjects will be inoculated with a total dose of 1000 tissue culture-infective dose 50% (TCID50) of rhinovirus (HRV) 39. The inoculum is diluted as appropriate in lactated Ringer's solution and delivered via a two step procedure: 0.25 ml per nostril is administered by pipette while the subject tilts their head back. It is anticipated that subjects will develop mild to moderate symptoms that are transient (lasting 3-7 days) and typically consist of nasal congestion, throat irritation, malaise and increased mucoid secretions. Subjects will record cold symptoms twice daily, using a diary card listing 8 symptoms, each of which are scored 0 to 3 on a basis of severity. Subjects will only be inoculated with HRV-39 once at Visit 5.

Biological: HRV-39

Interventions

HRV-39 BIOLOGICAL

We will use a US Food and Drug Administration (FDA) approved Good Manufacturing Practices (GMP)-grade HRV-39 for our proposed study. Use of this GMP-grade HRV-39 viral stock ensures compliance with recent regulatory agency requirements which, beginning in 2001, have mandated that HRV preparations used for human inoculation be made under Good Manufacturing Practices (GMP). This proposed clinical study will allow us to address fundamental questions regarding the nature, kinetics and potential mechanisms of upper and lower airway inflammatory responses in subjects with well-controlled mild-moderate asthma and in healthy, non-asthmatic control subjects; a better understanding of these mechanisms may lead to new paradigms in the treatment of virally-induced airway remodeling and asthma exacerbations.

Asthma Cohort; Healthy, Non-asthmatic Cohort

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

All potentially eligible study subjects will be screened for the presence of neutralizing serum antibodies to HRV-39 and only those subjects who are seronegative for HRV-39 will be included in either of the study cohorts: 1. Twelve non-smoking subjects with mild-moderate atopic asthma, aged 18-65 years, will be asked to volunteer for the study. 2. Twelve healthy non-smoking, non-allergic, non-asthmatic subjects, aged 18-65 years, will be asked to volunteer for the study.

You may qualify if:

• Male or female volunteers with intermittent or persistent mild to moderate allergic asthma, as defined by GINA guidelines.
• Between ≥18 and ≤ 65 years of age
• Objective evidence of variable airflow limitation (≥12% and at least 200mL post-bronchodilator reversibility from baseline) and airway hyperresponsiveness (PC20 methacholine \<16mg/mL) at screening or within past 5 years
• Spirometry at baseline shows FEV1 ≥ 60% of predicted; FEV1/FVC ≥ 0.40
• Atopic, as evidenced by positive skin prick tests to ≥1 common aero-allergen, where positive is defined by a wheal of ≥2 mm greater than the negative control
• Not be exposed to sensitizing seasonal allergens for at least 4 weeks before visit 2
• Asthma symptoms controlled by either inhaled beta 2-agonists alone, or by low or moderate dose (≤800 μg of budesonide or equivalent per day) inhaled corticosteroid (ICS) administered either as monotherapy or in a fixed-dose combination with a long-acting beta 2-agonist (LABA)
• Be a non-smoker for ≥1 year and have a lifetime ≤ 10 pack-year smoking history of smoking
• In good general health (other than asthma) without clinically significant medical history of other comorbidities, and a BMI of ≤ 35 kg/m2.
• Healthy, Non-asthmatic Cohort
• Male or female volunteers in good general health, without clinically significant medical history and a BMI of ≤ 35 kg/m2
• Between ≥18 and ≤ 65 years of age
• Non-asthmatic, as defined by history and normal spirometry (FEV1 ≥80% predicted; FEV1/FVC ≥ 0.75)
• Normal airway responsiveness (PC20 methacholine not detected at, or less than, 16 mg/mL)
• Non-atopic, as determined by skin prick tests to common aero-allergens, where a positive test is defined as a wheal of ≥2 mm greater than the negative control.

You may not qualify if:

• Presence of neutralizing antibodies to HRV-39
• Current pregnancy or positive urine pregnancy test at screening
• Use of any of the following medications: antihistamines, leukotriene antagonists, inhaled anticholinergics, non-steroidal anti-inflammatories, antibiotics, and over the counter 'cold' and influenza remedies, in preceding 4 weeks prior to visit 2.
• Current acute or chronic illness (including infection) or recent recovery (within 4 weeks of visit 3) from acute illness which could, in the opinion of the Investigator, alter inflammatory responses (e.g., flu, cold or other respiratory infection, etc.).
• Autoimmune disease or immunodeficiency
• Any other significant concomitant medical issue, or findings on physical examination or medical history 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.
• Inability or unwillingness of a potentially eligible study participant to give written informed consent.
• Unable or unwilling to adhere to protocol-defined study visit schedule and/or other protocol requirements.

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N4Z6, Canada

RECRUITING

Related Publications (34)

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MeSH Terms

Conditions

Asthma; Respiration Disorders

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 17, 2022
• First Posted: March 20, 2023
• Study Start: September 1, 2011
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: May 9, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)