AsthmaARRANCT05775952
Airway Remodeling and Rhinovirus in Asthmatics
An observational study of Asthma and Respiratory Disease, run by University of Calgary at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Asthma, Respiratory Disease
- What is being tested?
- HRV-39
- How many people
- 24 participants
- Where
- 1 siteCanada
- Study dates
- 1 Sep 2011to 31 Dec 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- 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
Show all 17Show fewer
- 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.
- Be a non-smoker for ≥1 year and have a lifetime ≤ 10 pack-year smoking history of smoking
- Willing to participate in study and be able to provide written consent prior to starting the study.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Canada1 site, 1 recruiting
- Recruiting
University of Calgary
Calgary, Alberta, T2N4Z6
Curtis Dumonceaux, 403-220-2123
Dr. Richard Leigh
About this study
Official title: Comparison of Airway Remodeling Mediators Following Experimental Human Rhinovirus Infection in Subjects With Mild to Moderate Asthma and Healthy, Non-asthmatic Control Subjects
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).
Read the detailed description
Airway remodeling is a characteristic feature of asthma, and refers to the structural changes that are present in the airways of asthmatic individuals. These changes are considered to be a major contributor to the pathophysiology of the episodic airway dysfunction, termed airway hyperresponsiveness (AHR) that is a hallmark of asthma. The traditional paradigm has, until recently, held that airway remodeling occurs after many years of chronic inflammation. However, more recently, studies have confirmed that remodeling changes are observed in children, in some instances even before the formal diagnosis of asthma is established. Moreover, there is now robust evidence to indicate that children with recurrent human rhinovirus (HRV)-induced wheezing episodes are at significantly increased risk of developing subsequent asthma. This has led us to hypothesize that HRV infections play a role in the development and subsequent continued progression of airway remodeling. In support of this paradigm-shifting hypothesis, we have published novel data, both in vitro and in vivo, establishing that HRV infections up-regulate airway epithelial cell production of several important mediators involved in airway remodeling remodeling processes.
A potential limitation of the in vivo studies reported by us to date is that these have involved healthy, non-asthmatic research participants studied during naturally-acquired HRV infections. Such studies are subject to seasonal variability and are difficult to perform in well-defined study populations, due to uncertainty regarding the onset of infection and the kinetics of subsequent host inflammatory responses. We therefore plan perform a Phase II clinical trial in which we will perform experimental HRV infections in subjects with mild-moderate asthma and in healthy control subjects. This will allow us to accurately study the kinetics of HRV-induced inflammatory and remodeling responses in a well characterized cohort of asthmatic subjects and compare these outcomes to those in a healthy, non-asthmatic control cohort. The primary study outcome will be 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 fluid (BALF) and endobronchial biopsy tissues and correlated with viral titres in both nasal lavage and BALF.
Airway epithelial cells are the primary site of HRV infection, and are the only cell type in which HRV has been detected thus far during in vivo infections. Moreover, there is unequivocal evidence that, following experimental nasal HRV inoculation, virus spreads to infect lower airway epithelial cells, providing a strong biological rationale for the proposed clinical study. HRV only replicate productively in vivo in humans and higher primates and even though rhinoviruses replicate in higher primates (chimpanzees and gibbons), infected animals do not show symptoms. Although two recent publications have reported induction of airway inflammation following exposure of mice to massive doses of unpurified HRV, these responses were transient with little evidence of sustained viral replication. Consequently, we hold the view that HRV only causes relevant infections in vivo in humans and it is for that reason that we continue to focus exclusively on human model systems for all our experimental work. A better understanding of in vivo HRV-induced airway remodeling mediators, and the mechanisms that regulate them, should extend our understanding of the role of HRV infections in the pathogenesis of airway remodeling in asthma.
Clinical studies involving the experimental infection of volunteers with rhinovirus have been conducted for more than 40 years. Challenge pools of rhinovirus for these experiments have generally been produced and safety tested according to guidelines published in 1964 and updated in 1992. The challenge pools produced under these guidelines appeared to be safe. Multiple studies have been conducted over this 40-year period in several countries. Dr. Proud has over 20 years of experience in conducting experimental HRV infection protocols. In the 40 years of such studies, it is reasonable to estimate that some 10,000 volunteers have been challenged worldwide to date, and no serious complications attributable to the viral infection have been detected. Moreover, nearly a dozen experimental HRV infection studies have been done in subjects with mild-moderate asthma over the past decade without serious complications. While these studies have contributed substantially to our understanding of rhinovirus-induced asthma symptoms, as well as of host inflammatory and antiviral responses, none have yet looked at the effects of experimental HRV infection on indices of airway remodeling.
Therefore, as a natural extension of our current research program and, in keeping with our expertise in HRV-related research, we now plan to perform this experimental rhinovirus infection study. We plan to use a US Food and Drug Administration (FDA) approved Good Manufacturing Practices (GMP)-grade HRV-39 (a gift from Dr. Ronald B. Turner, University of Virginia) 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.
- Conditions
- Asthma, Respiratory Disease
- Being tested
- HRV-39
- Keywords
- Human Rhinovirus
- Medical subject headings
- Asthma, Respiration Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HRV-39Biological
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Biological: HRV-39 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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+).
Measured: 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.
Measured: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Secondary outcomes (10)
Quantitative changes
Quantitative changes in gene expression, expressed in absolute units (e.g. attograms) between groups in lower airway secretions and tissues, as well as nasal scrapings, for selected airway remodeling mediator genes, including MMP-9, amphiregulin, VEGF and activin A.
Quantitative changes in gene expression, expressed in absolute units (e.g. attograms) between groups in lower airway secretions and tissues, as well as nasal scrapings, for selected novel airway remodeling mediator genes, identified by us to be unregulated by HRV infection on recent gene array studies
Measured: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Number of airway myofibroblasts
Changes in the number of airway myofibroblasts in bronchial biopsies following HRV-39 infection. We have recently reported a dramatic increase in the numbers of airway myofibroblasts 24 h post allergen challenge, and will now determine if similar changes occur in response to HRV infection.
Measured: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Changes in symptom scores - asthma control questionnaire (ACQ)
Changes in symptom scores (asthma control questionnaire (ACQ), measured on a scale from 1-6
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in cold symptom questionnaire
cold symptom questionnaire, measured on a scale of 1-6
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in viral titres
Viral titres (measured with TCDI50)
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in spirometry
spirometry (measured by FEV1/FVC; Asthma cohort, FEV1 ≥ 60% of predicted; FEV1/FVC ≥ 0.40; Non-asthmatic, FEV1 ≥80% predicted; FEV1/FVC ≥ 0.75)
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in airway responsiveness
Airway responsiveness (measured by methacholine challenge)
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in FeNO levels
FeNO levels (measured in ppb)
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Gene expression and protein levels
The correlation of gene expression and protein levels of selected mediators with viral titer, symptom scores and the numbers of inflammatory cells in the upper and lower airways.
Measured: Baseline (Visit 1) to Week 8 (Visit 11).
Quantitation of inflammatory cells in the lower airways, assessed in BALF and bronchial biopsies.
Quantitation of inflammatory cells in the lower airways, assessed in BALF and bronchial biopsies using FACS, H \& E staining to determine the adequacy and general morphology of the sample, Masson's Trichome stain and Picrosirius Red to demonstrate the presence of extracellular-matrix, and periodic acid Schiff (PAS) to demonstrate the presence of mucin within goblet cells.
Measured: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Mar 2023
- Study start1 Sep 2011
- Primary completion31 Dec 2024 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (34)Papers the sponsor has linked to this study.
- Other trials for AsthmaStudies of the same condition, open and under way.
- More trials run by University of CalgaryThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Calgary
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05775952
- Sponsor's protocol ID
- ARRA
- Acronym
- ARRA
- Status last verified
- May 2024
- First submitted
- 17 Nov 2022
- Last updated
- 9 May 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Leigh R, Oyelusi W, Wiehler S, Koetzler R, Zaheer RS, Newton R, Proud D. Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling. J Allergy Clin Immunol. 2008 May;121(5):1238-1245.e4. doi: 10.1016/j.jaci.2008.01.067. Epub 2008 Mar 19.
PubMed 18355907Tacon CE, Wiehler S, Holden NS, Newton R, Proud D, Leigh R. Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-kappaB. Am J Respir Cell Mol Biol. 2010 Aug;43(2):201-9. doi: 10.1165/rcmb.2009-0216OC. Epub 2009 Sep 25.
PubMed 19783786Turner RB, Hendley JO, Gwaltney JM Jr. Shedding of infected ciliated epithelial cells in rhinovirus colds. J Infect Dis. 1982 Jun;145(6):849-53. doi: 10.1093/infdis/145.6.849.
PubMed 6282984Bardin PG, Johnston SL, Sanderson G, Robinson BS, Pickett MA, Fraenkel DJ, Holgate ST. Detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization. Am J Respir Cell Mol Biol. 1994 Feb;10(2):207-13. doi: 10.1165/ajrcmb.10.2.8110476.
PubMed 8110476Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney JM Jr, Hayden FG. Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization. J Infect Dis. 1995 May;171(5):1329-33. doi: 10.1093/infdis/171.5.1329.
PubMed 7751712Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ, Meyer J, Lackie PM, Sanderson G, Holgate ST, Johnston SL. Rhinoviruses infect the lower airways. J Infect Dis. 2000 Jun;181(6):1875-84. doi: 10.1086/315513. Epub 2000 Jun 5.
PubMed 10837165Mosser AG, Vrtis R, Burchell L, Lee WM, Dick CR, Weisshaar E, Bock D, Swenson CA, Cornwell RD, Meyer KC, Jarjour NN, Busse WW, Gern JE. Quantitative and qualitative analysis of rhinovirus infection in bronchial tissues. Am J Respir Crit Care Med. 2005 Mar 15;171(6):645-51. doi: 10.1164/rccm.200407-970OC. Epub 2004 Dec 10.
PubMed 15591468Dick EC. Experimental infections of chimpanzees with human rhinovirus types 14 and 43. Proc Soc Exp Biol Med. 1968 Apr;127(4):1079-81. doi: 10.3181/00379727-127-32875. No abstract available.
PubMed 4297694Pinto CA, Haff RF. Experimental infection of gibbons with rhinovirus. Nature. 1969 Dec 27;224(5226):1310-1. doi: 10.1038/2241310a0. No abstract available.
PubMed 4311662Bartlett NW, Walton RP, Edwards MR, Aniscenko J, Caramori G, Zhu J, Glanville N, Choy KJ, Jourdan P, Burnet J, Tuthill TJ, Pedrick MS, Hurle MJ, Plumpton C, Sharp NA, Bussell JN, Swallow DM, Schwarze J, Guy B, Almond JW, Jeffery PK, Lloyd CM, Papi A, Killington RA, Rowlands DJ, Blair ED, Clarke NJ, Johnston SL. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat Med. 2008 Feb;14(2):199-204. doi: 10.1038/nm1713. Epub 2008 Feb 3.
PubMed 18246079Newcomb DC, Sajjan US, Nagarkar DR, Wang Q, Nanua S, Zhou Y, McHenry CL, Hennrick KT, Tsai WC, Bentley JK, Lukacs NW, Johnston SL, Hershenson MB. Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice. Am J Respir Crit Care Med. 2008 May 15;177(10):1111-21. doi: 10.1164/rccm.200708-1243OC. Epub 2008 Feb 14.
PubMed 18276942KNIGHT V. THE USE OF VOLUNTEERS IN MEDICAL VIROLOGY. Prog Med Virol. 1964;6:1-26. No abstract available.
PubMed 14310573Gwaltney JM Jr, Hendley O, Hayden FG, McIntosh K, Hollinger FB, Melnick JL, Turner RB. Updated recommendations for safety-testing of viral inocula used in volunteer experiments on rhinovirus colds. Prog Med Virol. 1992;39:256-63. No abstract available.
PubMed 1317600Naclerio RM, Proud D, Lichtenstein LM, Kagey-Sobotka A, Hendley JO, Sorrentino J, Gwaltney JM. Kinins are generated during experimental rhinovirus colds. J Infect Dis. 1988 Jan;157(1):133-42. doi: 10.1093/infdis/157.1.133.
PubMed 2447198Proud D, Gwaltney JM Jr, Hendley JO, Dinarello CA, Gillis S, Schleimer RP. Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds. J Infect Dis. 1994 May;169(5):1007-13. doi: 10.1093/infdis/169.5.1007.
PubMed 8169385
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Airway Remodeling Mediators Following Experimental Human Rhinovirus Infection in Subjects With Mild to Moderate Asthma and Healthy, Non-asthmatic Control Subjects
- ClinicalTrials.gov ID
- NCT05775952
- Acronym / sponsor ID
- ARRA / ARRA
- Conditions
- Asthma, Respiratory Disease
- Keywords
- Human Rhinovirus
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- University of CalgaryUniversity, hospital or other
- Study start
- 1 Sep 2011 (actual)
- Primary completion
- 31 Dec 2024 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 20 Mar 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
Airway remodeling is a characteristic feature of asthma, and refers to the structural changes that are present in the airways of asthmatic individuals. These changes are considered to be a major contributor to the pathophysiology of the episodic airway dysfunction, termed airway hyperresponsiveness (AHR) that is a hallmark of asthma. The traditional paradigm has, until recently, held that airway remodeling occurs after many years of chronic inflammation. However, more recently, studies have confirmed that remodeling changes are observed in children, in some instances even before the formal diagnosis of asthma is established. Moreover, there is now robust evidence to indicate that children with recurrent human rhinovirus (HRV)-induced wheezing episodes are at significantly increased risk of developing subsequent asthma. This has led us to hypothesize that HRV infections play a role in the development and subsequent continued progression of airway remodeling. In support of this paradigm-shifting hypothesis, we have published novel data, both in vitro and in vivo, establishing that HRV infections up-regulate airway epithelial cell production of several important mediators involved in airway remodeling remodeling processes.
A potential limitation of the in vivo studies reported by us to date is that these have involved healthy, non-asthmatic research participants studied during naturally-acquired HRV infections. Such studies are subject to seasonal variability and are difficult to perform in well-defined study populations, due to uncertainty regarding the onset of infection and the kinetics of subsequent host inflammatory responses. We therefore plan perform a Phase II clinical trial in which we will perform experimental HRV infections in subjects with mild-moderate asthma and in healthy control subjects. This will allow us to accurately study the kinetics of HRV-induced inflammatory and remodeling responses in a well characterized cohort of asthmatic subjects and compare these outcomes to those in a healthy, non-asthmatic control cohort. The primary study outcome will be 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 fluid (BALF) and endobronchial biopsy tissues and correlated with viral titres in both nasal lavage and BALF.
Airway epithelial cells are the primary site of HRV infection, and are the only cell type in which HRV has been detected thus far during in vivo infections. Moreover, there is unequivocal evidence that, following experimental nasal HRV inoculation, virus spreads to infect lower airway epithelial cells, providing a strong biological rationale for the proposed clinical study. HRV only replicate productively in vivo in humans and higher primates and even though rhinoviruses replicate in higher primates (chimpanzees and gibbons), infected animals do not show symptoms. Although two recent publications have reported induction of airway inflammation following exposure of mice to massive doses of unpurified HRV, these responses were transient with little evidence of sustained viral replication. Consequently, we hold the view that HRV only causes relevant infections in vivo in humans and it is for that reason that we continue to focus exclusively on human model systems for all our experimental work. A better understanding of in vivo HRV-induced airway remodeling mediators, and the mechanisms that regulate them, should extend our understanding of the role of HRV infections in the pathogenesis of airway remodeling in asthma.
Clinical studies involving the experimental infection of volunteers with rhinovirus have been conducted for more than 40 years. Challenge pools of rhinovirus for these experiments have generally been produced and safety tested according to guidelines published in 1964 and updated in 1992. The challenge pools produced under these guidelines appeared to be safe. Multiple studies have been conducted over this 40-year period in several countries. Dr. Proud has over 20 years of experience in conducting experimental HRV infection protocols. In the 40 years of such studies, it is reasonable to estimate that some 10,000 volunteers have been challenged worldwide to date, and no serious complications attributable to the viral infection have been detected. Moreover, nearly a dozen experimental HRV infection studies have been done in subjects with mild-moderate asthma over the past decade without serious complications. While these studies have contributed substantially to our understanding of rhinovirus-induced asthma symptoms, as well as of host inflammatory and antiviral responses, none have yet looked at the effects of experimental HRV infection on indices of airway remodeling.
Therefore, as a natural extension of our current research program and, in keeping with our expertise in HRV-related research, we now plan to perform this experimental rhinovirus infection study. We plan to use a US Food and Drug Administration (FDA) approved Good Manufacturing Practices (GMP)-grade HRV-39 (a gift from Dr. Ronald B. Turner, University of Virginia) 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.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Asthma Cohort | – | Biological: HRV-39Subjects 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. |
| Healthy, Non-asthmatic Cohort | – | Biological: HRV-39Healthy 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (17 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HRV-39We 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. | Biological | Asthma Cohort, Healthy, Non-asthmatic Cohort |
Primary outcome
The change between pre- and post-rhinoviral infection.
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
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.
Change of protein levels.
Time frame: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
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+).
The change in the lower airway secretions and tissues for selected airway remodeling mediators.
Time frame: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
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.
10 secondary outcomes
Quantitative changes
Time frame: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Number of airway myofibroblasts
Time frame: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Changes in symptom scores - asthma control questionnaire (ACQ)
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in cold symptom questionnaire
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in viral titres
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in spirometry
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in airway responsiveness
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Changes in FeNO levels
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Gene expression and protein levels
Time frame: Baseline (Visit 1) to Week 8 (Visit 11).
Quantitation of inflammatory cells in the lower airways, assessed in BALF and bronchial biopsies.
Time frame: Screening (Visit 4; Week 2) to infectious phase (Visit 9; Week 4).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2024.
- Background: PubMed 18355907Leigh R, Oyelusi W, Wiehler S, Koetzler R, Zaheer RS, Newton R, Proud D. Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling. J Allergy Clin Immunol. 2008 May;121(5):1238-1245.e4. doi: 10.1016/j.jaci.2008.01.067. Epub 2008 Mar 19.
- Background: PubMed 19783786Tacon CE, Wiehler S, Holden NS, Newton R, Proud D, Leigh R. Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-kappaB. Am J Respir Cell Mol Biol. 2010 Aug;43(2):201-9. doi: 10.1165/rcmb.2009-0216OC. Epub 2009 Sep 25.
- Background: PubMed 6282984Turner RB, Hendley JO, Gwaltney JM Jr. Shedding of infected ciliated epithelial cells in rhinovirus colds. J Infect Dis. 1982 Jun;145(6):849-53. doi: 10.1093/infdis/145.6.849.
- Background: PubMed 8110476Bardin PG, Johnston SL, Sanderson G, Robinson BS, Pickett MA, Fraenkel DJ, Holgate ST. Detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization. Am J Respir Cell Mol Biol. 1994 Feb;10(2):207-13. doi: 10.1165/ajrcmb.10.2.8110476.
- Background: PubMed 7751712Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney JM Jr, Hayden FG. Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization. J Infect Dis. 1995 May;171(5):1329-33. doi: 10.1093/infdis/171.5.1329.
- Background: PubMed 10837165Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ, Meyer J, Lackie PM, Sanderson G, Holgate ST, Johnston SL. Rhinoviruses infect the lower airways. J Infect Dis. 2000 Jun;181(6):1875-84. doi: 10.1086/315513. Epub 2000 Jun 5.
- Background: PubMed 15591468Mosser AG, Vrtis R, Burchell L, Lee WM, Dick CR, Weisshaar E, Bock D, Swenson CA, Cornwell RD, Meyer KC, Jarjour NN, Busse WW, Gern JE. Quantitative and qualitative analysis of rhinovirus infection in bronchial tissues. Am J Respir Crit Care Med. 2005 Mar 15;171(6):645-51. doi: 10.1164/rccm.200407-970OC. Epub 2004 Dec 10.
- Background: PubMed 4297694Dick EC. Experimental infections of chimpanzees with human rhinovirus types 14 and 43. Proc Soc Exp Biol Med. 1968 Apr;127(4):1079-81. doi: 10.3181/00379727-127-32875. No abstract available.
- Background: PubMed 4311662Pinto CA, Haff RF. Experimental infection of gibbons with rhinovirus. Nature. 1969 Dec 27;224(5226):1310-1. doi: 10.1038/2241310a0. No abstract available.
- Background: PubMed 18246079Bartlett NW, Walton RP, Edwards MR, Aniscenko J, Caramori G, Zhu J, Glanville N, Choy KJ, Jourdan P, Burnet J, Tuthill TJ, Pedrick MS, Hurle MJ, Plumpton C, Sharp NA, Bussell JN, Swallow DM, Schwarze J, Guy B, Almond JW, Jeffery PK, Lloyd CM, Papi A, Killington RA, Rowlands DJ, Blair ED, Clarke NJ, Johnston SL. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat Med. 2008 Feb;14(2):199-204. doi: 10.1038/nm1713. Epub 2008 Feb 3.
- Background: PubMed 18276942Newcomb DC, Sajjan US, Nagarkar DR, Wang Q, Nanua S, Zhou Y, McHenry CL, Hennrick KT, Tsai WC, Bentley JK, Lukacs NW, Johnston SL, Hershenson MB. Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice. Am J Respir Crit Care Med. 2008 May 15;177(10):1111-21. doi: 10.1164/rccm.200708-1243OC. Epub 2008 Feb 14.
- Background: PubMed 14310573KNIGHT V. THE USE OF VOLUNTEERS IN MEDICAL VIROLOGY. Prog Med Virol. 1964;6:1-26. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Asthma and Respiratory Disease, run by University of Calgary at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The change between pre- and post-rhinoviral infection. (time frame: Baseline (Visit 1) to Week 8 (Visit 11).). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05775952, which also lists 34 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2024.