Viral Infection in Asthma (VIA) Study

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).

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 39.
• Willing and able to comply with clinic visits and study-related procedures
• Provide informed consent signed by study patient
• Able to understand and complete study-related questionnaires

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
• Members of the clinical site study team and/or his/her immediate family
• Pregnant or breastfeeding women
• Women of childbearing potential* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last dose. Highly effective contraceptive measures include:

• stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening
• intrauterine device (IUD); intrauterine hormone releasing system (IUS)
• bilateral tubal ligation
• vasectomized partner and/or

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• sexual abstinence†, ‡.

• Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.

• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.