Effects of Intranasal Fluticasone Plus Azelastine on Airway Inflammation in Patients With Asthma & Allergic Rhinitis

Study Overview
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Brief Summary
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Single centre, double-blind, placebo controlled, adaptive design, cross-over trial. The primary objective is to assess the additive effects of using combined intranasal fluticasone propionate plus azelastine nasal spray on airway hyperresponsiveness. This is in patients with persistent asthma and allergic rhinitis, receiving inhaled steroid.

Detailed Description
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The unified allergic airway describes patients who have both asthma and allergic rhinitis. Both conditions have similar underlying pathophysiology in terms of T-helper 2 (Th2) cell activation. Patients with unified allergic airway disease have a greater burden in terms of impaired quality of life, and the presence of airway hyper-responsiveness (AHR) to methacholine is a hallmark of their underlying asthmatic inflammatory process. Targeting the Th2 allergic airway with a topical antihistamine may improve airway hyperresponsiveness. It has previously been shown that in patients with unified allergic airway disease, using inhaled fluticasone alone (100 micrograms per day) produced a 1.2 doubling dilution (dd) shift in the provocative concentration of methacholine required to reduce forced expiratory volume (FEV1) by 20% (PC20). However when adding nasal fluticasone to the inhaled steroid, there was a 1.79 dd shift. This difference (0.58 dd, 95% CI 0.78, 1.95) was not statistically significant. However the combined treatment did result in significant improvement in rhinitis quality of life, nasal inflammation and inspiratory flow. The investigators will repeat this previous concept, but compare intranasal fluticasone with azelastine (an antihistamine) nasal spray versus placebo nasal spray, in atopic asthmatic patients on inhaled steroid. This will be to assess effects on methacholine PC20, the primary outcome, and to assess the effects on the following secondary outcomes: Exhaled nitric oxide (FeNO), FEV1, morning peak expiratory flow (PEF), impulse oscillometry, peak nasal inspiratory flow (PNIF), nasal nitric oxide (NO), blood eosinophils, eosinophilic cationic protein (ECP), nasal symptoms, asthma control and quality of life; and rhinitis quality of life. Twenty adults 18 and up, with allergic asthma will be enrolled. They will have a run-in on 2 weeks of 200 micrograms beclometasone inhaler and then be randomised to add either intranasal fluticasone and azelastine, or placebo nasal spray to their treatment (double blind). Treatment period one will be 3-5 weeks followed by a washout of 2-4 weeks, and crossover to treatment period two for 3-5 weeks. Due to the crossover nature of this study participants will receive both treatments in random order. There will be an Interim analysis after 20 participants complete the study per protocol and the exact required sample size will be recalculated (Pocock/adaptive design).

Official Title
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Proof of Concept Study to Assess Downstream Effects of Using Combined Intranasal Fluticasone Propionate Plus Azelastine Nasal Spray on Asthmatic Inflammation in Patients With Persistent Asthma and Allergic Rhinitis

Conditions
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Asthma, Allergic, Rhinitis,Allergic, Allergy

Intervention / Treatment
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* Drug: Azelastine-Fluticasone Nasal
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female volunteers, aged 18 years and above, with persistent asthma and allergic rhinitis On a minimum of 200μg BDP of Inhaled corticosteroid (ICS) FEV1 ≥ 60 % predicted Positive skin prick test, or record of elevated allergen-specific IgE to at least 1 perennial allergen Methacholine PC20 < 8mg/ml at Visit 1 Ability to give informed consent Exclusion Criteria: Other respiratory diseases such as COPD, bronchiectasis or allergic bronchopulmonary aspergillosis (ABPA) which are considered to be significant in the opinion of the study physician Nasal polyps ≥ Grade 2 An asthma exacerbation or respiratory tract infection requiring systemic steroids and/or antibiotics within 1 month of the study commencement, or 3 months if hospital admission was required Any clinically significant medical condition that may endanger the health or safety of the participant. For example: Patients who have tuberculosis or any type of untreated infection or have had recent surgical operation or injury to the nose or mouth. Participation in another trial within 30 days before the commencement of the study Pregnancy or lactation Unable to comply with the procedures of the protocol Unable or unwilling to consent Taking prohibited medications as listed in section 6.7.2 Prohibited Medications Hypersensitivity to the active substances or to any of the excipients of Dymista Nasal Spray.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azelastine-Fluticasone Nasal<br>137 micrograms azelastine hydrochloride / 50 micrograms fluticasone propionate per actuation. 1 squirt twice daily | Drug: Azelastine-Fluticasone Nasal<br>* 137 micrograms azelastine hydrochloride / 50 micrograms fluticasone propionate<br>* Other names: Dymista;|
| Placebo Comparator: Placebos<br>contains the same components as Dymista nasal spray with the exception of the active ingredients. 1 squirt twice daily. | Drug: Placebos<br>* Placebo nasal spray<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methacholine PC20 | The provocative concentration of methacholine required to produce a 20% drop (PC20) in forced expiratory volume in 1 second (FEV1) | 3-5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exhaled nitric oxide (FeNO) | A measurement of the amount of inflammation in the airways | 3-5 weeks | 
| Forced expiratory volume in 1 second (FEV1) | The amount of air exhaled in the first second of a forced expiration. | 3-5 weeks | 
| Morning peak expiratory flow (PEF) | A measurement of how quickly a patient can blow air out of their lungs | 3-5 weeks | 
| Airway resistance at 5Hz (R5) | A measurement of the total airway resistance at the frequency of 5 Hertz | 3-5 weeks | 
| Airway resistance at 20Hz (R20) | A measurement of the proximal airways resistance at the frequency of 20 Hertz | 3-5 weeks | 
| Peripheral airway resistance (R5-R20) | A measurement of the peripheral airway resistance by taking the resistance at 5Hz and subtracting the resistance at 20 Hertz | 3-5 weeks | 
| Airway Reactance (X5) | A measurement of the peripheral capacitive reactance at the frequency of 5 Hertz | 3-5 weeks | 
| Airway Reactance area under the curve (AX) | A measurement of the reactance area between the negative reactance trend and zero. | 3-5 weeks | 
| Domiciliary peak nasal inspiratory flow (PNIF) | A measurement of how open or blocked the nasal passages are. | 3-5 weeks | 
| Nasal nitric oxide (NO) | A measurement of the amount of inflammation in the nasal passages. | 3-5 weeks | 
| Blood eosinophils | A measurement of the amount of eosinophils in the blood | 3-5 weeks | 
| Eosinophilic cationic protein (ECP) | A measurement of the amount of Eosinophilic Cationic Protein (ECP) in the blood | 3-5 weeks | 
| Total nasal symptom score (TNS4) | A questionnaire to assess four (4) types of nasal symptoms: runny nose, blocked nose, itchy nose, and sneezing. | 3-5 weeks | 
| Asthma control questionnaire (ACQ) | A questionnaire to measure the degree of a person's asthma control | 3-5 weeks | 
| Asthma quality of life questionnaire (AQLQ) | A questionnaire to measure the functional problems that are most troublesome to adults with asthma. | 3-5 weeks | 
| Rhinitis quality of life questionnaire (RQLQ) | A questionnaire to measure the functional problems that are most troublesome to adults with rhinitis. | 3-5 weeks | 
| Visual analogue scale (VAS) | a 10 cm line horizontal describing rhinitis symptoms. zero being not bothersome and ten being very bothersome. | 3-5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Rhinitis, Dymista, allergy