Effect of Montelukast on Experimentally-Induced RV16 Infection in Asthma

Study Overview
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Brief Summary
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People with asthma may have asthma worsening when they have an upper respiratory infection due to a virus or a common cold. Leukotrienes are increased in nasal secretions from children with Respiratory Syncytial Virus (RSV) and lung washings during times of acute lung inflammation. Experimental virus exposure in adults is also associated with increases in nasal leukotrienes. The degree to which leukotrienes play a role in asthma worsening is unknown.There is information linking leukotrienes to viral infections, allergic inflammation, and asthma exacerbation.This information supports the hypothesis that virus-induced leukotrienes contribute to the severity of respiratory infections and in susceptible individuals, lead to lower airway obstruction and exacerbations of asthma. We propose to use montelukast in an experimental viral challenge model to explore this hypothesis.

Detailed Description
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Viral infections are important causes of wheezing illnesses throughout childhood and in adults with asthma. There has been progress in identifying mechanisms and risk factors for severe respiratory symptoms, and in particular, wheezing. Given this close relationship, it would be attractive to apply antiviral strategies to the prevention and treatment of asthma, and both RV and RSV are obvious targets. Unfortunately, attempts at developing an RSV vaccine have so far been unsuccessful, and vaccination to prevent RV infection does not seem to be feasible due to the large number of serotypes. Antiviral medications have been tested in clinical trials, however one problem with this approach is that once the clinical signs and symptoms appear, viral replication is well underway. The other potential therapeutic approach for respiratory viral infections would be to selectively inhibit pro-inflammatory immune responses induced by the virus. The beneficial effects of systemic glucocorticoids indicate that this approach is valid; the challenge will be to develop treatments with greater efficacy and a reduced potential for adverse effects. The large body of information linking cysteinyl leukotrienes to viral infections, allergic inflammation, and asthma exacerbations, strongly supports the hypothesis that virus-induced leukotrienes contribute to the severity of respiratory infections and in susceptible individuals, lead to lower airway obstruction and exacerbations of asthma. We propose to use montelukast in an experimental viral challenge model to explore this hypothesis.

Official Title
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Effect of Montelukast on Experimentally-Induced RV16 Infection in Volunteers With Mild Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: montelukast
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject with mild persistent asthma is eligible for participation in the study if all of the following inclusion criteria apply: Male or female with no health concerns that might affect the outcome of the study Age 18-65 range diagnosis of mild persistent asthma based on clinical findings such as cough, wheeze and shortness of breath a history of asthma for at least six months prior to screening FEV1> 80% of predicted presence of allergy based on at least one positive prick skin test when tested with a standard panel of common allergens ability to produce sputum when induced during the baseline assessments asthma medications consisting of only inhaled short acting B-agonist taken as needed reversible airways disease as indicated by > 12% reversibility post B-agonist or methacholine hyperresponsiveness (PC20 < 8 mg/ml) ability to give valid informed consent to participate by signing and dating a written consent form Exclusion Criteria: A subject is not eligible to participate in this study if any of the following exclusion criteria apply: History of severe episodes of asthma with respiratory infections Screening serum RV16 antibody titer > 1 Current smoker or has a smoking history exceeding 5 pack years Currently receiving immunotherapy Currently participating in another clinical trial or has participated in an investigational drug trial within one month of screening Unable, in the judgment of the investigator, to comply with directions and/or tolerate the procedures required for participation in this trial Pregnant or breast-feeding or has a planned pregnancy during the course of the study Regular use of an asthma controller such as montelukast or an inhaled corticosteroid.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Montelukast<br>montelukast (10 mg everyday) | Drug: montelukast<br>* 10 mg everyday<br>* Other names: Singulair;|
| Placebo Comparator: Placebo<br>Placebo comparator | Drug: placebo<br>* like placebo<br>* Other names: like placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Asthma Symptom Score | Asthma symptom scores were assessed twice per day with subjects completing a validated daytime diary card before bed and a nocturnal diary card on awakening. Subjects answered 4 questions about their asthma symptoms (0, none of the time; 6, all of the time). Daily score were calculated as the average of the 4 questions and an overall score for the week was assessed as the average of the daily scores. Time frame measurement was Day 7. | Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Viral Shedding | Viral shedding was measured in both groups. Viral titers from nasal lavage were calculated after 4 tissue culture tubes containing WI38 cells (human lung diploid cells) were inoculated for each serial 10-fold dilution of samples and incubated while rolling at 33 degrees Celsius for 10 days (measurement for analysis was taken at baseline and 7 days). Tubes were read at baseline and 7 days later. TCID50 was calculated as the concentration that was capable of infecting 50% of the tubes. Viral titers are expressed as TCID50 per milliliter. Time frame measurement was at baseline and 7 days. | Baseline and 7 days | 
| Sputum Eosinophil Count | Sputum was collected from both groups over 14 days after inoculation with the cold virus. Cell counts and differentials were made from sputum samples after treatment with 0.1% dithiothreitol. Eosinophils were counted and are expressed as as percentage of cells (percent of the total number counted) at the 14 day timepoint. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, leukotrienes, rhinovirus