Viral Infection in Asthma (VIA) Study
Overview
- Phase
- Phase 4
- Status
- Recruiting
- Sponsor
- University of Virginia
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Change in interleukin-25 transcript expression post-rhinovirus inoculation
Overview
Brief Summary
Often when people with asthma get a virus caused by the common cold (rhinovirus), they also experience an increase or worsening of their asthma symptoms. The purpose of this study is to see if the study medication dupilumab helps prevent those with mild to moderate asthma from having increased asthma symptoms, after being exposed to an experimental rhinovirus inoculation. This is a study about dupilumab which is a drug approved by the U.S. Food and Drug Administration (FDA) for treatment of moderate to severe asthma. Dupilumab is a medication that blocks pathways that cause asthmatic inflammation in the lungs, leading to symptoms and worsening lung function. During this study, subjects will be given either dupilumab or placebo and will subsequently be exposed to the the "common" cold virus (rhinovirus). The virus that the investigators are using has been safely used before in many studies like this involving thousands of volunteers, and the safe use of the virus in this research study has been reviewed by the FDA. The investigators will track asthma symptoms during the study with lung function tests, questionnaires, specimen collection, biomarkers, and physical exams. For data analysis the investigators will assess the samples collected to determine changes in the treatment groups. The investigators will also asses the symptom scores and deviations from baseline measures for lung function.
Detailed Description
Rhinovirus (RV) is responsible for up to 70-80% of asthmatic exacerbations in children and adolescents requiring urgent care or hospitalizations. Understanding the mechanism by which this otherwise relatively innocuous infection produces asthma exacerbations is essential towards mitigating these episodes. Two theories have been proposed to explain this phenomenon. One is that asthmatics have defective innate and adaptive immune responses to viral respiratory infections, leading to increased viral-associated pathology with an associated enhanced inflammatory response. An alternative - and not mutually exclusive - explanation is that RV indirectly exacerbates an ongoing allergic response to bystander allergens. Dupilumab blocks type 2 inflammatory responses and is known to prevent asthma exacerbations. It both attenuates the reduced innate immunity observed in asthmatics and also reduces the ability to engage a type 2 allergic inflammatory response to bystander allergens. Therefore, the investigators hypothesize that RV mediated worsening of asthma will be attenuated in the presence of dupilumab. This study examines cellular and molecular mediators of these interactions, which could help understand the intimate mechanism(s) underlying dupilumab's protective effect in asthmatics.
A total of 60 patients with mild persistent asthma will be enrolled and randomized in this study (30 active treatment and 30 placebo).
The double-blind, randomized design minimizes any sources of bias. The placebo group provides a reference for the interpretation of study results, so the net effect of dupilumab could be discerned. The dupilumab dose regimen selected for this study (300 mg q2w after an initial loading dose of 600 mg) is consistent with the approved dose for patients with asthma. The primary objective of the study is to evaluate the effect of dupilumab on innate antiviral and type 2 inflammatory biomarkers, epithelial barrier repair, and adaptive immune responses following rhinovirus infection in asthmatic patients. The exploratory objectives include evaluating the effect of dupilumab in reducing the severity of rhinovirus-induced respiratory symptoms, its effect on lung function (eg FEV1, FEV1/FVC) and asthma control. As well as evaluating the effect of dupilumab on other biomarkers and viral load. The sample size was selected empirically, informed by similar successful studies conducted in the past. For example, in a previous double-blind, placebo-controlled randomized trial of omalizumab in the prevention of RV-induced asthma exacerbations, a total n of 20 (10 per group in the final analysis) was sufficient to achieve a secondary endpoint based on FEV1/FVC ratio). These data demonstrate the intrinsic power of the viral challenge model. The population included in the current trial has been further enriched (mild to moderate persistent asthmatics, on ICS ± other long-term controllers).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
The placebo group provides a reference for the interpretation of study results, so the net effect of dupilumab could be discerned.
Eligibility Criteria
- Ages
- 18 Years to 40 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Adult ages 18-40
- •Physician diagnosed asthma for at least 6 months
- •Mild persistent asthma well controlled (ACT≥20) over 6-month period prior to enrollment
- •FEV1 of \>80% predicted
- •Well controlled asthma on albuterol alone or albuterol plus low to medium dose inhaled corticosteroids (ICS) with or without other controller medications not using any anti-inflammatory medications for any concurrent sinonasal conditions.
- •Positive methacholine test (≤16 mg/ml)
- •Blood eosinophil count ≥150/µL or FeNO ≥20 ppb
- •Negative (≤1:4) serum neutralizing HRV antibody to HRV 16 or HRV
- •Willing and able to comply with clinic visits and study-related procedures
- •Provide informed consent signed by study patient
Exclusion Criteria
- •Current smoker or has smoked regularly for 10 yrs and smoked \>10 pack-years
- •History or clinical evidence of COPD or any other significant lung disease
- •Known allergy to any ingredients in the study drug product
- •Asthma biologic therapy in last 3 months (including dupilumab)
- •Antiviral, immunosuppressive, or immune modulator therapies in the last 3 months
- •Use of any inhaled nasal sprays
- •Upper or lower respiratory tract infection in the last 6 weeks
- •Asthma exacerbation in the last 6 weeks
- •Any history of an asthma exacerbation requiring Emergency Department visit, intubation or hospitalization
- •History of asthma exacerbation requiring unscheduled office visit or oral corticosteroids within the past 3 years
Arms & Interventions
Dupilumab
The dupilumab dose regimen selected for this study (300 mg q2w after an initial loading dose of 600 mg)
Intervention: Dupilumab Injectable Product (Drug)
Placebo
A harmless substance that looks like the study drug, but which should have no effect. The placebo formulation used in this study contains all the ingredients present in the active drug, except the active ingredient (IL-4α antibody). Therefore, the risk related to this formulation should be no greater than the risk associated to the active drug.
Intervention: Dupilumab Injectable Product (Drug)
Outcomes
Primary Outcomes
Change in interleukin-25 transcript expression post-rhinovirus inoculation
Time Frame: Day 0 to day 4 post-inoculation with the rhinovirus
Comparison of the change in IL-25 transcript expression in nasal scraping samples as determined by semi-quantitative polymerase chain reaction between the placebo- and dupilumab-treated cohorts
Secondary Outcomes
- Change in allergen-specific Th2 effector lymphocytes post-rhinovirus inoculation(Day 0 to day 14)
- Change in symptoms post-rhinovirus inoculation(Day 0 to day 14)
- Change in transcriptome in nasal brushing samples post-rhinovirus inoculation(Day 0 to day 14 post-inoculation with the rhinovirus)
- Change in the proteome in nasal wash samples post-rhinovirus inoculation(Day 0 to day 14 post-inoculation with the rhinovirus)
Investigators
Larry Borish, MD
M.D. Professor of Medicine and Microbiology Asthma and Allergic Disease Center
University of Virginia