Dymista Allergen Chamber - Onset of Action Study

Study Overview
=================
Brief Summary
-----------------
This study is to assess the onset of action of fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray (Dymista) in treating the nasal symptoms of seasonal allergic rhinitis (SAR) induced by an allergen challenge in an Environmental Exposure Unit (EEU).

Official Title
-----------------
Clinical Trial to Assess Onset of Action of Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray Delivered in a Single Spray (Dymista) in the Treatment of Allergen-Induced Allergic Rhinitis Symptoms in Comparison to Placebo in an Environmental Exposure Unit (EEU)

Conditions
-----------------
Seasonal Allergic Rhinitis

Intervention / Treatment
-----------------
* Drug: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 3
* Drug: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 5
* Drug: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 5
* Drug: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 3


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide written informed consent. Male or female subjects (childbearing and non-childbearing potential, non-childbearing potential defined as females with no menstruation for at least 1 year at screening and documented Follicle-Stimulating Hormone (FSH) > 35 IU/L) aged 18 to 55 years (inclusive) at screening. History of SAR to ragweed pollen for at least the previous 2 ragweed pollen seasons. Positive skin prick test (SPT) response to ragweed pollen (allergen induced wheal diameter at least 3 mm larger than the negative control). A test performed at Cliantha Research in the previous 12 months may be used to qualify the subject. Willingness to complete all study visits. To be eligible for Visit 2 EEU, a subject must additionally comply with the following criteria: Asymptomatic or with mild symptoms during the baseline recording of symptoms prior to start of the screening EEU (Visit 2): • Total Nasal Symptom Score (TNSS) ≤ 3/12 with the score for each symptom being less than 2. To be eligible for Visit 3, a subject must additionally comply with the following criteria during Visit 2 EEU: Demonstrate adequate symptomology: • TNSS ≥ 6/12 on at least two Electronic Patient Data Acquisition Tablet (ePDAT TM) time point assessments during hours 0-2 in the EEU (Visit 2), with at least one occurring during the last two time points. Additionally, subjects will be required to meet a score of at least 2/3 for runny nose at least twice during hours 0-2 in the EEU, with at least one occurring during the last two time points. To be eligible for randomization (Visit 3), a subject must additionally comply with the following criteria: Demonstrate adequate symptomology: TNSS ≥ 6/12 on at least two ePDATTM time point assessments during hours 0-2 in the EEU (Visit 3), with at least one occurring during the last two time points. Additionally, subjects will be required to meet a score of at least 2/3 for runny nose at least twice during hours 0-2 in the EEU, with at least one occurring during the last two time points. No evidence of complete nasal blockage on either one or both sides on anterior rhinoscopy within 30 minutes prior to dosing. Exclusion Criteria: Safety concerns: History of allergic reaction to azelastine hydrochloride or fluticasone propionate or one of the excipients of the study treatments (e.g. benzalkonium chloride, phenylethyl alcohol, microcrystalline cellulose) or a component of the container. History of anaphylaxis, cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrine, metabolic, psychiatric, neurological, or other disease at screening that may affect subject safety during the study or evaluation of the study endpoints at the discretion of the Investigator and/or designee. Subjects with a current diagnosis of asthma or subjects with measured Forced Expiratory Volume in 1 Second (FEV1) <75% of the predicted value using Global Lung Function Initiative set from 2012 for references. Pregnant, breast-feeding or planning a pregnancy during the study and women of childbearing potential not using adequate contraception. Women of childbearing potential not abstinent or using a highly effective method of birth control defined as those which result in a low failure rate (i.e. <1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal Intrauterine Devices (IUDs), barrier methods, or tubal ligation started at least 4 weeks prior to screening. Lack of suitability for the study: Previous and concomitant treatments: use of prohibited therapies (Antihistaminic agents, all presentations; Theophylline, all presentations; Cromolyn sodium, all forms; Nedocromil sodium; Salbutamol, all presentations; Leukotriene modifiers, all presentations; Corticosteroids (inhaled, oral, intravenous); Topical corticosteroids (ocular, intranasal); Corticosteroids (intramuscular or intra-articular); Decongestants, all forms; Immunotherapy; Systemic antibiotics; Tricyclic antidepressants and Monoamine Oxidase (MAO) inhibitors; Any cytochrome P450 3A4 inhibiting or inducing drug (e.g. ritonavir, cobicistat, ketoconazole, itraconazole, erythromycin, cimetidine, rifampicin, St. John's wort (Hypericum perforatum) etc.) not allowed within specific time frames prior to Screening and/or not allowed/allowed only with restrictions during the study, as specified in the study protocol; use of any medication considered to have an influence on the outcome of the study during the EEU session, at the discretion of the Investigator and/or designee. Subjects with (expected) clinically relevant symptoms at the timing of the scheduled EEU assessments due to concomitant allergies, i.e. history of allergic response to the causative allergen, at the discretion of the Investigator. Subjects with a positive SPT for cats and/or dogs are acceptable if the subject avoids cats and/or dogs for the duration of the study. Concomitant diseases: abnormalities during the screening visit (Visit 1) or Visit 2 that might interfere with study results as determined by the Investigator and/or designee. Presence of a severely deviated septum, septal perforation, structural nasal defect or large nasal polyps causing obstruction as determined by the Investigator. Acute conditions: any acute illness within 7 days prior to the screening visit (Visit 1) or Visit 2, including acute conjunctivitis or any other ocular infection, at the discretion of the Investigator and/or designee. History of increased ocular pressure, glaucoma, cataracts, and/or central serous chorioretinopathy (CSCR). Presence of or ongoing tuberculosis, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections or ocular herpes simplex. Recent nasal ulcers, mucosal erosion, nasal surgery, or nasal trauma, that might interfere with study results as determined by the Investigator and/or designee. Exposure to chickenpox or measles within 4 weeks prior to the screening visit or during the study. Acute or chronic sinusitis or non-allergic rhinitis, at the discretion of the Investigator and/or designee. Exposure to another investigational product within the last 30 days prior to screening. History of malignancy within the past five years, except for basal cell skin carcinomas that have been treated with no recurrence for at least 3 months. Neurological or psychiatric disease or drug or alcohol abuse which would interfere with the subject's proper completion of the protocol assignment. Subjects with a positive urine drug screen will be excluded. Subjects undergoing surgical procedures with general anaesthesia within 90 days prior to screening or who plan to undergo surgery/hospitalization during the study. Administrative reasons: Vulnerable subjects (such as persons who are institutionalized). Positive alcohol or drug test during screening visit (Visit 1) Public health emergency (e.g. COVID-19): subjects not complying to Public health guidelines (e.g. self isolation etc.), at the discretion of the Investigator's and/or designee, or subjects with a positive COVID-test at Visit 2.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study will be a single-center, randomized, placebo-controlled, double-blind, and two-period cross-over trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A (Dymista) and Treatment B (Placebo), separated by at least 14 days of wash-out period<br>Fixed drug combination of Azelastine hydrochloride 137 μg / Fluticasone propionate 50 μg nasal spray and Placebo nasal spray | Drug: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 3<br>* Single dose, one spray in each nostril of Dymista nasal spray, approximately 137 μg of azelastine hydrochloride and 50 μg of fluticasone propionate per actuation, at Visit 3<br>Drug: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 5<br>* Single dose, one spray in each nostril of Placebo nasal spray at Visit 5<br>|
| Experimental: Treatment B (Placebo) and Treatment A (Dymista), separated by at least 14 days of wash-out period<br>Placebo nasal spray and Fixed drug combination of Azelastine hydrochloride 137 μg / Fluticasone propionate 50 μg nasal spray | Drug: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 5<br>* Single dose, one spray in each nostril of Dymista nasal spray, approximately 137 μg of azelastine hydrochloride and 50 μg of fluticasone propionate per actuation, at Visit 5<br>Drug: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 3<br>* Single dose, one spray in each nostril of Placebo nasal spray, at Visit 3<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-assessed Instantaneous Total Nasal Symptom Score (TNSS) From Baseline Compared to Placebo | FDA guideline defines onset of action as the first time point after initiation of treatment when the product demonstrated a greater change from baseline compared to placebo which proved durable. In this study, the first significant difference to placebo of TNSS was observed at 5 minutes time point (= onset of action). The TNSS is comprised of 4 symptoms from the nose, each scored on a scale of 0 to 3 (0 = none and 3 = severe). The sum of the TNSS contributes to a score ranging from 0 - 12. | 0 to 4 hours post application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-assessed Instantaneous Total Ocular Symptom Score (TOSS) From Baseline Compared to Placebo | FDA guideline defines onset of action as the first time point after initiation of treatment when the product demonstrated a greater change from baseline compared to placebo which proved durable. In this study, the first significant difference to placebo of TOSS was observed at 10 minutes time point (= onset of action). The TOSS is comprised of 3 symptoms from the eyes, each scored on a scale of 0 to 3 (0 = none and 3 = severe). The sum of the TOSS contributes to a score ranging from 0 - 9. | 0 to 4 hours post application |