Evaluating Factors Involved in Dymista's Superior Clinical Efficacy to Fluticasone Propionate in the Treatment of Seasonal Allergic Rhinitis

Study Overview
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Brief Summary
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Dymista, a combined product containing the antihistamine azelastine and the intranasal steroid fluticasone, provides superior clinical efficacy to both fluticasone propionate and azelastine hydrochloride in the treatment of seasonal allergic rhinitis. The superiority of efficacy not only occurs at the initiation of treatment, but persists for its duration. The mechanism underlying the superior efficacy of Dymista is not known. This trial focuses on examining the effects of Dymista on the dynamics of the allergic response in man using nasal provocation with antigen. The investigators will study the relationship between symptoms, physiology, cells and mediators.

Detailed Description
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The main hypothesis for the trial is that Dymista affects multiple phases of the allergic response, which in sum are greater than the effects of fluticasone propionate or azelastine hydrochloride alone. Our objectives for this study are to demonstrate: that the induction of allergic inflammation by nasal provocation with antigen causes a cellular infiltration, with subsequent release of inflammatory biomarkers that cause augmented responses to subsequent exposure to antigens. that fluticasone prevents allergic inflammation from developing after antigen challenge and subsequently prevents the augmentation of the nasal response to nasal challenge with antigen. that the azelastine in Dymista reduces the effects of released histamine To address these hypotheses we will perform a 3-way, randomized, placebo-controlled, and crossover trial. We will recruit 20 asymptomatic seasonal allergic rhinitis patients outside of the relevant season. The subjects will receive placebo, fluticasone propionate and Dymista. The nasal provocations will be separated by 2 weeks. Treatment will begin 15 minutes before nasal provocation with ragweed or grass antigen and the treatment will continue twice a day for 3 days. Nasal provocation will occur daily for three days to evaluate for priming (increased sensitization with repeated antigen exposure, which mimics seasonal disease where antigen exposure occurs in the setting of continued allergic inflammation). For outcome measures, we will monitor both nasal symptoms after nasal provocation as well as collect nasal lavage to evaluate effects on eosinophils and biomarkers of the immune response. In the nasal lavage, we will quantify the number of eosinophils (a marker of cellular recruitment) and measure the levels of histamine (a marker of basophil and mast cell activation), tryptase (a marker of mast cell activation), albumin (a marker of vascular permeability), lactoferrin (a marker of glandular activation) and ECP (a marker of eosinophil activation). Thus we expect to generate information on both clinical effects and physiologic differences between the treatments.

Official Title
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Evaluating Factors Involved in Dymista's Superior Clinical Efficacy to Fluticasone Propionate in the Treatment of Seasonal Allergic Rhinitis

Conditions
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Allergic Rhinitis

Intervention / Treatment
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* Drug: Placebo
* Drug: Fluticasone propionate
* Drug: Fluticasone/Azelastine nasal spray
* Procedure: Nasal Allergen Challenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between 18 and 55 years of age. History of grass and/or ragweed allergic rhinitis. Positive skin test to grass and/or ragweed antigen. Positive response to screening nasal challenge. Off all anti-allergic medications for a minimum of 2 weeks. Exclusion Criteria: Physical signs or symptoms suggestive of renal, hepatic or cardiovascular disease. Pregnant or lactating women. Upper respiratory infection within 14 days of study start.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo nasal spray that is similar to Dymista in all respects except the active ingredient | Drug: Placebo<br>* Patients will be treated by placebo<br>Procedure: Nasal Allergen Challenge<br>* All subjects will receive a nasal challenge with allergen to mimick an allergic response and allow the investigation of the different drug effects on that response. Allergen extracts will be used as sprays into the nasal cavity. The extracts are approved by FDA for skin testing or desensitization therapy and an IND was obtained to allow intranasal administration<br>|
| Experimental: Fluticasone propionate<br>Fluticasone propionate nasal spray provided in a bottle similar to placebo and dymista | Drug: Fluticasone propionate<br>* Patients will receive fluticasone nasal spray<br>Procedure: Nasal Allergen Challenge<br>* All subjects will receive a nasal challenge with allergen to mimick an allergic response and allow the investigation of the different drug effects on that response. Allergen extracts will be used as sprays into the nasal cavity. The extracts are approved by FDA for skin testing or desensitization therapy and an IND was obtained to allow intranasal administration<br>|
| Experimental: Dymista (fluticasone/azelastine)<br>Dymista is also provided as a nasal spray in bottles similar to the other two agents | Drug: Fluticasone/Azelastine nasal spray<br>* Patients will receive Dymista nasal spray<br>* Other names: Dymista;Procedure: Nasal Allergen Challenge<br>* All subjects will receive a nasal challenge with allergen to mimick an allergic response and allow the investigation of the different drug effects on that response. Allergen extracts will be used as sprays into the nasal cavity. The extracts are approved by FDA for skin testing or desensitization therapy and an IND was obtained to allow intranasal administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Albumin level in nasal lavage | We will calculate the total change of albumin levels after the allergen challenges and subtract the diluent (sham) response for a single value that will reflect the increase in vascular permeability after allergen challenges on the first day after treatment with the 3 different agents. This will be compared between therapies | Change in Albumin level after the first nasal challenge on each treatment arm. The nasal challenge consists of a diluent challenge followed by 2 allergen challenges and lavages are collected 10 minutes after each of these challenges | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sneezes after allergen challenge | We will evaluate the effects of the different interventions on the number of sneezes after allergen challenges | Number of sneezes after allergen challenges. The nasal challenge consists of a diluent challenge followed by 2 allergen challenges and sneezes are counted in a 10 minute period after each of the challenges |