Study of Airway Inflammatory Responses to Experimental Rhinovirus Infection
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|ClinicalTrials.gov Identifier: NCT03508479|
Recruitment Status : Suspended (Suspended due to COVID-19.)
First Posted : April 25, 2018
Last Update Posted : May 18, 2021
|Condition or disease||Intervention/treatment||Phase|
|Healthy Volunteers Rhinovirus||Biological: RG-HRV16||Phase 1|
The majority of severe exacerbations of asthma and need for hospitalizations are triggered by infection with respiratory viruses. Of these, rhinovirus is the most commonly implicated virus. Furthermore, there is evidence that viral infections exert synergistic effects with other stimuli to provoke asthma symptoms such as exposure to allergens and air pollutants. Experimental HRV infection studies have yielded important insights into the underlying disease mechanisms of viral-induced asthma exacerbations, and have been integral to identifying candidates for the development of new therapies. These studies have been safely conducted in both healthy and susceptible populations (those with underlying airway disease such as asthma and chronic obstructive pulmonary disease (COPD)), for more than 60 years.
Much of the understanding of the clinical course of HRV infection is derived from experimental infections of healthy human volunteers. In these studies, subjects were inoculated intranasally with up to 10,000 [tissue culture infectious dose (TCID)] TCID50 of HRV, the most commonly used strains being HRV-16 and HRV-39. Experimental HRV infection produces the hallmark clinical features of the common cold including rhinorrhea and nasal obstruction. Respiratory symptoms typically develop 1-2 days after inoculation. Cold symptom scores generally peak 2-4 days post infection and return to baseline within 1 week in most infected subjects. HRV infection induces changes in inflammatory cell recruitment, nasal cytokine levels, and gene expression, which occur concurrently with clinical symptoms.
While the symptoms of HRV infection are typically limited to the upper respiratory tract in healthy subjects, those with underlying airway disease such asthma and COPD are more likely to exhibit an augmented and prolonged response to HRV infection with lower airway involvement. HRV is the leading viral cause of exacerbations of asthma and COPD; therefore, the response of these populations to HRV infection has been the focus of a number of studies. Although most studies in asthmatics have been performed in inhaled corticosteroid-naïve subjects, a recent study performed in subjects whose asthma was well controlled with inhaled corticosteroids demonstrates the safety of experimental HRV infection in this population. This model has also been employed in conjunction with other exposure models such as allergen challenge and pollutant exposure. There are several ongoing and recently completed clinical trials registered with ClinicalTrials.gov that utilize the HRV infection model. Of these, several employ the HRV-16 strain (ClinicalTrials.gov Identifiers: NCT01769573, NCT01466738, NCT01823640, NCT03073837, NCT03296917, NCT01704040, NCT02910401) being used in this study. Both healthy and asthmatic volunteers are represented in these clinical trials.
In summary, the experimental HRV infection model has proven to be a safe and valuable tool for examining various aspects of HRV biology. Due to the limitations associated with animal models of asthma and COPD, and the lack of animal species that are permissive for HRVs, experimental infection of humans with HRV has been integral for examining the pathophysiology of virus-induced exacerbations of asthma and COPD. Although experimental HRV-infection results in a reduction in lung function for some asthmatics and COPD patients, no serious adverse events have been reported using this model.
The goal of this study is to establish the experimental HRV-infection model in this research center using a viral inoculum referred to as RG-HRV-16. This strain was used in a recently-completed safety and dosing study (NCT01769573). Our study would provide the pilot data needed for the design of subsequent studies evaluating innate immune responses to HRV infection in asthmatics, modulation of HRV-induced responses by inhaled pollutants, and efficacy of novel therapeutic agents.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||23 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Study of Airway Inflammatory Responses to Experimental Rhinovirus Infection|
|Estimated Study Start Date :||March 2022|
|Estimated Primary Completion Date :||June 2023|
|Estimated Study Completion Date :||July 2023|
Experimental: RG-HRV16 Inoculation
While wearing a dental bib, subjects will be asked to blow the nose prior to inoculation. With the head tilted back, a total of 0.5 mL (0.25 mL/nostril) will be administered using the MAD Nasal™ Intranasal Mucosal Atomization Device. Subjects instructed not to blow nose for 30 minutes afterwards.
0.25 mL inoculum intranasally delivered into each nostril (0.5 mL total delivered). Total cumulative dose of 1000 median tissue culture infective dose at 50% of cells inoculated (TCID50).
Other Name: Rhinovirus Type 16
- Change in neutrophils/mL in nasal lavage fluid from baseline to mean of days 2-4 post inoculation [ Time Frame: Baseline and study visit days 2-4 ]Nasal lavage fluid will be collected at baseline. Participants will then undergo RG-HRV16 inoculation. Nasal lavage fluid will be collected on days 2-3 post inoculation and mean neutrophils/ml over days 2-4 will be compared to baseline.
- Mean Symptom Score from Cold Symptom Questionnaire up to 4 weeks post-inoculation [ Time Frame: 4 weeks post-inoculation ]Assessment of eight clinical symptoms on the day of RG-HRV16 inoculation and days 2, 3, 4, 7, 14, 28 following inoculation will be performed with a cold symptom questionnaire. Scores of 0, 1, 2, or 3 will be given to symptoms rated as absent, mild, moderate, or severe, respectively. Minimum score: 0. Maximum score: 32.
- Change in FEV1 and FEF25-75% from baseline to 4 weeks post-inoculation [ Time Frame: Baseline and 4 weeks post-inoculation ]Changes in FEV1 and FEF25-75% (mean forced expiratory flow between 25% and 75% of the FVC or maximum mid-expiratory flow) from baseline will be assessed up to 4 weeks post-RG-HRV16 inoculation (on days 2, 3, 4, 7, 14, and 28 following inoculation).
- Change in Methacholine reactivity, as measured by the concentration of methacholine resulting in a 20% drop in FEV1 (PC20), from baseline to day 4 post-inoculation [ Time Frame: Baseline and study visit day 4 (post-inoculation) ]Participants will undergo a methacholine challenge to assess airway hyper-responsiveness at baseline. Changes in methacholine reactivity, as measured by the PC20, from baseline to 4 days after RG-HRV16 inoculation will be determined.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03508479
|United States, North Carolina|
|UNC Center for Environmental Medicine, Asthma and Lung Biology|
|Chapel Hill, North Carolina, United States, 27599-7310|
|Principal Investigator:||Michelle Hernandez, MD||University of North Carolina|