- Email: [email protected]
Effect of olopatadine-mometasone combination nasal spray on seasonal allergic rhinitis symptoms in an environmental exposure chamber study
Accepted Manuscript
Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study Piyush Patel MD , Anne Marie Salapatek PhD , Sudeesh K. Tantry PhD PII: DOI: Reference:
S1081-1206(18)31308-5 https://doi.org/10.1016/j.anai.2018.10.011 ANAI 2722
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
29 May 2018 1 October 2018 9 October 2018
Please cite this article as: Piyush Patel MD , Anne Marie Salapatek PhD , Sudeesh K. Tantry PhD , Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study, Annals of Allergy, Asthma Immunology (2018), doi: https://doi.org/10.1016/j.anai.2018.10.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study
Piyush Patel, MD1 Anne Marie Salapatek, PhD1 Sudeesh K. Tantry, PhD2 Inflamax Research Inc, Mississauga, Ontario, CA; 2Glenmark Pharmaceuticals, Paramus, NJ,
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Corresponding Author: Piyush Patel, MD 1310 Fewster Drive Mississauga, ON, L4W 1A4
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Tel: 905-282-6310 Fax: 905-206-2690
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Email: [email protected]
Conflicts of Interest: Piyush Patel, MD is the CEO and Principal Scientist at Inflamax Research
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(Mississauga, ON, CA, a member of Cliantha Research) and was the site principal investigator on this trial funded by Glenmark Pharmaceuticals. Anne Marie Salapatek, PhD is the Executive
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Vice President and Chief Science Officer for Inflamax Research (Mississauga, ON, CA, a member of Cliantha Research) and was involved in the design and conduct of this study funded by Glenmark Pharmaceuticals. Sudeesh K. Tantry is an employee of Glenmark Pharmaceuticals. Funding: Glenmark Specialty SA
ACCEPTED MANUSCRIPT 2 Acknowledgments Assistance with medical writing, editing, and formatting of the manuscript for submission was provided by Lynn M. Anderson, PhD of Prescott Medical Communications Group (Chicago, IL)
Trial Registration: ClinicalTrials.gov, NCT03444506
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and funded by Glenmark Specialty SA.
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Abstract: BACKGROUND: GSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate intended for seasonal allergic rhinitis (SAR) treatment. OBJECTIVE: Efficacy and safety of GSP301 once-daily (QD) or twice-daily (BID) were evaluated in a ragweed pollen Environmental Exposure Chamber (EEC). METHODS: In this randomized, double-blind, double-dummy study, adults (18-65 years) with SAR were equally randomized to GSP301 BID (olopatadine 665μg/mometasone 25μg), GSP301 QD (olopatadine 665μg/mometasone 50μg), AzeFlu (FDA-approved azelastine 137μg/fluticasone 50μg BID), Olopatadine (FDA-approved formulation 665μg BID), or placebo (BID). During two visits (baseline and end of 14-day treatment), participants assessed SAR symptoms at specified time points. The primary endpoint—mean change from baseline in instantaneous Total Nasal Symptom Score (iTNSS) for GSP301 BID or QD versus placebo—was analyzed by ANCOVA. Onset of action, ocular symptoms, and adverse events (AEs) were assessed. RESULTS: A total of 180 participants were randomized. Treatment with GSP301 BID or QD provided statistically significant improvements in iTNSS versus placebo (least squares mean difference [95% CI] GSP301 BID: -3.60 [-4.89, -2.30]; QD: -3.05 [-4.35, -1.76]; P<0.0001, both). Significant improvements in iTNSS with GSP301 BID occurred by 10 minutes post-dose (1.26 [-2.30, -0.21], P=0.019) and were maintained at all later time points except one (2.5 hours). Treatment-emergent AEs occurred in 22.2%, 30.6%, 25.0%, 22.2%, and 16.7% of participants in GSP301 BID, GSP301 QD, AzeFlu, Olopatadine, and placebo groups, respectively. CONCLUSION: In an EEC model, GSP301 BID and QD treatments were well tolerated and provided statistically significant and clinically meaningful SAR symptom improvement versus placebo.
Keywords (up to 12; up to 5 phrases): combination nasal spray; seasonal allergic rhinitis; olopatadine; mometasone; environmental exposure chamber; ragweed pollen; onset of action
ACCEPTED MANUSCRIPT 3 INTRODUCTION Allergic rhinitis (AR) is an inflammatory disease1 affecting 20 million adults2 and 6 million children3 in the US. The economic burden of AR is substantial with total annual expenditures in 2005 estimated at $11.2 billion (USD), driven primarily by prescription drug costs.4 Further
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adding to this burden, AR symptoms can negatively impact quality of life through decreased work/school productivity, disturbed sleep, fatigue, irritability, and depression.5,6
Although pharmacological options to treat AR are available, symptom control is
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inadequate for many patients. Of patients who reported using at least one prescription allergy treatment, 47% were using two or more agents, and many frequently supplemented with nonprescription allergy treatments.5 Since nasal symptoms (congestion, rhinorrhea, itching and sneezing) and non-nasal symptoms (itching/burning, tearing/watering, and redness of eyes;
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itching of ears/palate) can occur within minutes of allergen exposure, medications that provide both immediate and sustained relief with minimal side effects are essential for effective disease
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management.5 Combining a fast-acting intranasal antihistamine with a long-acting intranasal
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corticosteroid may be more effective in controlling AR symptoms than monotherapy treatment.7,8 Using a single-device combination treatment in place of multiple monotherapy agents may also
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reduce healthcare costs9 (depending on local pricing) and improve treatment adherence.10,11
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GSP301 is a fixed-dose combination (FDC) of the antihistamine olopatadine hydrochloride (HCl) and the corticosteroid mometasone furoate developed as a single nasal spray for the treatment of seasonal AR (SAR) symptoms. Olopatadine is a well-tolerated, highly selective histamine H1-receptor antagonist with anti-inflammatory properties12 that, when applied intranasally, reduces itchy/runny nose and sneezing.13,14 The intranasal corticosteroid mometasone effectively reduces SAR symptoms of nasal itching and congestion, sneezing, and
ACCEPTED MANUSCRIPT 4 rhinorrhea by inhibiting the release of inflammatory mediators and has a well-documented safety profile with minimal systemic effects.15-18 The efficacy and safety of US Food and Drug Administration (FDA)-approved olopatadine HCl (Olopatadine) and mometasone furoate monotherapy nasal sprays have been demonstrated in natural allergen-exposure studies13,14,17,19
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as well as in studies using an Environmental Exposure Chamber (EEC).20-22
The objective of this study was to evaluate the efficacy and safety of GSP301 once-daily (QD) or twice-daily (BID) treatments versus placebo and two FDA-approved nasal sprays,
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Olopatadine23 and AzeFlu (an FDC containing the antihistamine azelastine HCl and the
glucocorticoid fluticasone propionate),24 in participants with SAR using a ragweed pollen EEC model. The advantage of an EEC study over a natural allergen-exposure study is that participants with AR can be exposed to an allergen of choice, allowing for consistent allergen level exposure
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over the entire course of the study, as well as continual monitoring of participant compliance with procedures and treatments. An EEC study controls the inherent variability that is present in
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natural allergen-exposure studies.25
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METHODS
This study (NCT03444506) was conducted in accordance with the Declaration of Helsinki Good
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Clinical Practice (GCP) according to International Conference on Harmonization (ICH)
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guidelines. The protocol received ethical clearance from the Institutional Review Board Services (Aurora, Ontario, Canada) and was carried out according to applicable local regulatory requirements. All participants provided written informed consent.
ACCEPTED MANUSCRIPT 5 Study Design and Assessments This was a randomized, single-site, double-blind, double-dummy, placebo-controlled, parallelgroup proof-of-concept study conducted outside of the ragweed pollen season (January/February). The study consisted of a screening visit, five EEC visits (priming, pre-dose,
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post-dose, and two post-12-day at-home dosing), and 12 days of at-home dosing (Figure 1). Participants were dosed for a total of 14 days. Exposure to airborne ragweed pollen (3500 ± 500 particles/m3) occurred for 6 hours in an EEC at visits 2 (pre-treatment priming), 3, 4 (post-
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treatment priming), and 5. At visit 3, participants were in the EEC for 6 hours in order to develop SAR symptoms, upon which eligible participants were equally randomized to one of the following treatments: GSP301 BID (sponsor olopatadine 665 μg/sponsor mometasone 25 μg); GSP301 QD (sponsor olopatadine 665 μg/sponsor mometasone 50 μg); AzeFlu BID (azelastine
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137 μg/fluticasone 50 μg; FDA-approved formulation); Olopatadine BID (665 μg; FDAapproved formulation); or placebo BID (based on the GSP301 formulation). Participants were
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provided with 4 nasal spray bottles (2 for AM dosing and 2 for PM dosing) and self-administered
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1 spray/nostril from each bottle every day. For AzeFlu dosing (1 spray/nostril vs 2 sprays/nostril), 2 bottles of AzeFlu (1 for AM and 1 for PM) and 2 bottles of placebo (1 for AM
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and 1 for PM) were provided to maintain blinding. Participants administered their first treatment under observation at the research site for 2 days. Thereafter, double-blinded treatments were self-
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administered over 12 days at home, without symptom assessment. To evaluate efficacy, SAR nasal and ocular symptoms were assessed by participants in the EEC during four clinic visits (visits 2, 3, 4 and 5) at prespecified time points. Participants rated how they felt at the time of the assessment (ie, instantaneous symptoms) using the instantaneous Total Nasal Symptom Score (iTNSS) and the instantaneous Total Ocular Symptom Scores (iTOSS) in
ACCEPTED MANUSCRIPT 6 an electronic dairy (Figure 1). Symptoms were rated on a scale of 0 (absent) to 3 (severe; see supplemental Table S1). Nasal symptoms included congestion, rhinorrhea, itching and sneezing; ocular symptoms included itching/burning, tearing/watering, and redness of eyes.
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Participants Eligible participants included adults aged 18 to 65 years with a clinical history of SAR for at least 2 years for ragweed pollen who had a positive skin prick test for ragweed (wheal diameter ≥3 mm than negative control). Participants were not required to be mono-sensitized to ragweed
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pollen. At the screening/priming visit (visit 2), participants must have met a minimum iTNSS ≥6 out of 12 (including a score of ≥2 for nasal congestion) on ≥2 consecutive diary entries; at the randomization visit (visit 3), participants must have met a minimum iTNSS ≥6 out of 12 (including a score of ≥2 for nasal congestion) on at least 1 diary entry in the first 6 hours of the
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EEC session.
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Key exclusion criteria consisted of: known history of acute or significant chronic sinusitis, chronic purulent post-nasal drip, rhinitis medicamentosa, nasal surgery, or nasal
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structural abnormalities including ulceration, mucosal erosion, large polyps or marked septal deviations that significantly interfered with nasal air flow. Participants could not be dependent on
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nasal, oral, or ocular decongestants, nasal topical antihistamines or nasal steroids or use
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inhaled/systemic corticosteroids chronically (excluding ≤8 puffs/day of inhaled short-acting βagonists). Furthermore, participants could not have a history of seasonal asthma during ragweed season or a known history of hypothalamic-pituitary-adrenal axis disease or dysfunction. Use of the following medications was not permitted 5 days prior to initial dosing: antihistamines, anticholinergics, or products containing ephedrine, pseudoephedrine or decongestants. The following medications were not permitted for up to 30 days prior to dosing:
ACCEPTED MANUSCRIPT 7 ocular, intranasal, or systemic corticosteroids (7, 14, or 30 days prior, respectively); leukotriene inhibitors, cromolyn, or systemic antibiotics (14 days prior); immunosuppressants/modulators (30 days prior). Immunoglobulin E antagonists could not be used for 120 days prior to initial dosing. Use of intranasal therapies, topical corticosteroids, ophthalmic drops, clinical trial drugs,
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radiation therapy, injectable immunotherapy, rescue medications for AR control (ie,
oral/intranasal antihistamines or anticholinergics, intranasal corticosteroids, decongestants, or ephedrine/pseudoephedrine-containing products), or exposure to cytochrome P450 3A4
inhibiting or inducing drugs (eg, carbamazepine, dexamethasone, phenytoin, rifabutin, rifampin,
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pioglitazone) were not permitted at any time during the study. Consumption of food or drink containing grapefruit, orange, apple, mustard green family vegetables, alcohol, and charbroiled meat was not permitted during study participation.
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Endpoints
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The primary endpoint was the mean change from baseline (visit 3) to end of treatment (visit 4) in post-dose iTNSS for GSP301 BID and QD versus placebo. Secondary endpoints included mean
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change from baseline to end of treatment in post-dose iTNSS for: GSP301 BID and QD versus AzeFlu and versus Olopatadine; AzeFlu and Olopatadine compared with placebo.
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Additional secondary endpoints included evaluation of onset of action and ocular
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symptom assessment. Onset of action for each treatment was determined by the mean change from baseline in iTNSS versus placebo at 5, 10, 15, 20, 25, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, and 4 hours after the first dose of study treatment (in the 4 hours post-dose at visit 3). Ocular symptoms (itching, tearing/watery eyes, redness) were assessed through mean change from baseline (visit 3) to end of treatment (visit 5) in post-dose iTOSS for: GSP301 BID and QD versus placebo; GSP301 BID versus AzeFlu and Olopatadine; and GSP301 QD versus AzeFlu
ACCEPTED MANUSCRIPT 8 and Olopatadine. Safety was monitored through ear, nose and throat examinations, as well as adverse event (AE) reporting. Statistical Analysis
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Efficacy analyses were based on the intention-to-treat (ITT) population, defined as all randomized participants who received ≥1 dose of study drug and completed ≥1 efficacy
assessment during treatment. Safety assessments were based on the safety population, which included all participants who received ≥1 dose of study drug. Baseline demographic variables
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and AEs were summarized by treatment group using descriptive statistics. Change from baseline in mean post-treatment iTNSS was examined by analysis of covariance (ANCOVA) with baseline as a covariate and treatment as a fixed effect. Baseline was defined as the average of symptom scores over 6 hours in the EEC at visit 3 immediately prior to the first dose (day 1). A
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treatment difference that reached P<0.05 was considered statistically significant (referred to as
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“significant”) and a treatment difference of at least 0.23 units on TNSS was considered clinically meaningful using direct anchor-based methodology (defined as the minimal clinically important
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difference).26 Onset of action was defined as the first of two consecutive time points after initiation of treatment when the drug demonstrated a significant difference in iTNSS compared
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to the placebo as long as the significant difference was sustained. Onset was analyzed using ANCOVA with baseline as a covariate and treatment as a fixed effect. Baseline was
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characterized as the average of the last two predose time points at visit 3 (-1.0 h and -0.5 h). Change from baseline in mean post-treatment iTOSS was also analyzed using ANCOVA, with baseline as a covariate and treatment as a fixed effect. All tests were two-sided using a significance level of 5% and all analyses were conducted using SAS® (v 9.2 or higher). Sample Size
ACCEPTED MANUSCRIPT 9 To detect a between-treatment difference of 1.65 units in the mean change from baseline in iTNSS for the primary endpoint (GSP301 versus placebo; over 6 hours in the EEC) at visit 5 with a standard deviation of 2.24 units and with a power of 0.80, at least 30 evaluable participants needed to be randomized to each group (150 participants total; based on unpublished
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data on file). A total of 180 participants were enrolled, assuming a drop-out rate of 15%. RESULTS Participants
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A total of 180 participants were randomized (n=36 in each treatment group), with mean ages ranging from 38.3 to 44.9 years across treatments (Table 1). At baseline, participants had moderate to severe SAR symptoms, with mean iTNSS ranging from 7.6 to 8.7 and mean iTOSS ranging from 4.2 to 4.8 (Table 1). One participant in the GSP301 QD group discontinued the
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study due to a family emergency and 3 participants (2 in the AzeFlu group and 1 in the placebo
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group) discontinued due to failure to follow study procedures. Efficacy
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iTNSS
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For the primary endpoint, treatment with GSP301 BID or QD showed statistically significant and clinically meaningful improvements in iTNSS versus placebo (P<0.0001, both; Table 2). These
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improvements were sustained during the entire 6-hour post-treatment EEC session (Figure 2). For the secondary endpoints, significant improvement in iTNSS occurred with AzeFlu compared with placebo (P<0.0001; Table 2); Olopatadine versus placebo yielded clinically meaningful, but not statistically significant, improvement in iTNSS (P=0.18; Table 2). GSP301 BID and QD showed significant and clinically meaningful improvements in iTNSS versus Olopatadine
ACCEPTED MANUSCRIPT 10 treatment (LSMD [95% CI] GSP301 BID: -2.94 [-4.23, -1.64], P<0.0001; QD: -2.39 [-3.69, 1.10], P=0.0004). Similar clinically meaningful improvements were observed with GSP301 BID and QD compared with AzeFlu, but these did not reach statistical significance (GSP301 BID: 1.09 [-2.46, 0.28], P=0.118; QD: -0.53 [-1.90, 0.83], P=0.441).
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Onset of Action
A significant difference in change from baseline in iTNSS occurred at 10 minutes post-dose for GSP301 BID versus placebo (LSMD [95% CI]: -1.26 [-2.30, -0.21], P=0.019), and was
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maintained at 11 out of the 12 subsequent time points (P<0.05, all); the change from baseline in iTNSS did not reach statistical significance only at the 2.5-hour assessment (P=0.065; Figure 3). The improvements with GSP301 BID were clinically meaningful at all time points. There were no statistically significant differences in change from baseline in iTNSS between the other active
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treatments (GSP301 QD, AzeFlu, and Olopatadine) and placebo at any time point, with the
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exception of GSP301 QD at 3 and 4 hours post-dose (P=0.04 and P=0.01, respectively; data not shown) and Olopatadine at 10 minutes post-dose only (P=0.01; data not shown).
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iTOSS
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Treatment with GSP301 BID or QD resulted in significant ocular symptom (iTOSS) improvements versus placebo (LSMD [95% CI] BID: -1.64 [-2.60, -0.68], P<0.0001; QD: -1.20
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[-2.15, -0.24], P=0.015). GSP301 BID significantly improved ocular symptoms versus Olopatadine (P=0.04) but not versus AzeFlu (data not shown). Safety
The percentage of participants reporting ≥1 treatment emergent AE (TEAE) was generally comparable among the treatment groups, with a slightly greater percentage in the GSP301 QD
ACCEPTED MANUSCRIPT 11 group (Table 3). Headache and dysgeusia were the most frequently reported TEAEs and occurred similarly across treatments except for a greater percentage in the GSP301 QD (headache) and BID (dysgeusia) groups versus placebo. All TEAEs were mild to moderate and none led to study discontinuation. No serious adverse events (SAEs) or deaths were reported.
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DISCUSSION
Developing effective treatments for AR is important as symptom control is often inadequate, with many patients requiring more than one prescription medication or additional treatments.5,6
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Studies have shown that combining a nasal spray antihistamine and corticosteroid may be more effective in reducing AR symptoms than monotherapy alone.27-31 Furthermore, combined (FDC) treatment in a single-device may reduce medical and pharmacy costs (depending on local pricing) compared with using multiple monotherapies.9
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Results from this proof-of-concept study demonstrated that the FDC containing
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mometasone furoate and olopatadine hydrochloride in a single nasal spray (GSP301) delivered BID or QD provides significant and clinically meaningful26 nasal symptom improvement versus
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placebo in participants with moderate to severe SAR exposed to ragweed in an EEC. Statistically significant improvements with GSP301 BID were rapid, occurring within 10 minutes of dosing.
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Rapid significant symptom relief was maintained at 11 of the 12 subsequent time points during
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the 4-hour assessment period; the assessment at 2.5 hours did not reach statistical significance (P=0.06). GSP301 BID and QD also significantly improved ocular symptoms compared with placebo.
These results complement those observed in later natural allergen exposure SAR studies with GSP301 where dosing BID30-32 or QD30 provided significant, clinically meaningful,26 and sustained nasal symptom improvements. Furthermore, the results from a large, phase 2 natural
ACCEPTED MANUSCRIPT 12 allergen exposure study demonstrated that GSP301 BID was the optimally safe and efficacious dosage regimen.30 GSP301 BID also demonstrated a rapid onset of action (15 minutes – first time point tested post-dose) in the natural allergen studies that was maintained at all subsequent time points assessed.30-32 Furthermore, GSP301 BID provided significant improvements in ocular
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symptoms in two large SAR studies conducted in different pollen seasons.33 Overall, the results from the current study combined with those of natural-allergen exposure studies demonstrate that GSP301 provides rapid, clinically meaningful improvements in SAR nasal symptoms as well as significant ocular symptom improvements in multiple pollen seasons and under different
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exposure conditions (ie, EEC versus natural allergen).
In addition to demonstrating nasal symptom improvement over placebo, GSP301 BID and QD provided clinically meaningful26 nasal symptom improvement versus the commercially
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available AzeFlu and Olopatadine treatments, but only comparisons with Olopatadine were statistically significant. As expected, AzeFlu and Olopatadine both demonstrated clinically
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meaningful26 improvements in nasal symptoms versus placebo, though the comparison of
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Olopatadine versus placebo did not reach statistical significance. The reason for the nonsignificance in some of these comparisons is unclear. As noted earlier, the current study was
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powered at 80% and a larger sample size may be necessary to assess the efficacy of all treatment comparisons. It should also be noted that the placebo formulation used in this study was based on
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the GSP301 vehicle rather than the reference treatments. However, in later adequately powered phase 2 and 3 natural allergen-exposure SAR studies, an olopatadine formulation (BID) made with the GSP301 vehicle (sponsor olopatadine formulation) provided significant and clinically meaningful improvements in nasal symptoms versus placebo.30,31
ACCEPTED MANUSCRIPT 13 The desire among AR patients for rapid and long-lasting symptom relief5 can be achieved by combining an antihistamine and a corticosteroid into a single intranasal formulation. Indeed, intranasal formulations of antihistamines and corticosteroids are efficacious monotherapies that differ in onset of action, with antihistamines providing immediate but short-term symptom relief
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(15−30 minutes) and corticosteroids providing sustained symptom relief with a longer onset of action (3−36 hours).1 Combining these monotherapies into one treatment allows for both
immediate and sustained relief. For example, the FDA-approved combination treatment AzeFlu has an onset of action of 30 minutes29 whereas the individual monotherapies, azelastine and
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fluticasone, have onsets of 15 minutes34 and 12 hours,35 respectively.
In the current study, onset of action was defined as the first of two consecutive time points after initiation of treatment at which the drug demonstrated a significant reduction in
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iTNSS compared to placebo that was sustained. GSP301 BID treatment resulted in significant and clinically meaningful symptom improvement versus placebo at 10 minutes and significance
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was maintained at 11 of the 12 subsequent time points over the 4-hour assessment. Historically,
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the interpretation has been that onset of action can still be defined even if the treatment difference does not reach statistical significance at all time points during the time course as long
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as the difference is considered sustained.22,36 For GSP301 BID, the first of two consecutive time points that were significantly different from placebo occurred at 10 minutes, which is
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considerably shorter than the onset of action reported in studies of the component monotherapies: olopatadine monotherapy has been shown to have an onset of action of 30 minutes21-23 while onset for mometasone ranges from 150 minutes (EEC study)21 to 11 hours (natural allergen and EEC studies).37 In two large, phase 3 natural allergen exposure SAR studies of GSP301 BID, onset of action was observed at the earliest time point assessed (15 minutes
ACCEPTED MANUSCRIPT 14 after the first dose) and was sustained at all later time points of onset evaluation session.33 When combined with the findings from the current study, there is evidence that GSP301 has a shorter onset of action than reported for either of the component monotherapies. In this study, significant and clinically meaningful iTNSS improvements seen at 10
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minutes with GSP301 BID were shorter than the onset of action reported for the marketed
combination nasal spray, azelastine hydrochloride/fluticasone propionate (AzeFlu) in a natural allergen exposure study (10 minutes for GSP301 versus 30 minutes for AzeFlu). However, in a
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specifically designed EEC study, TNSS for AzeFlu versus placebo was significantly reduced to 5 minutes.38 Onset of action for GSP301 QD, AzeFlu and Olopatadine were not determined in the current study, however, as significant differences in iTNSS change from baseline between these treatments and placebo were not observed at any two consecutive time points. The reason for
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these varying results is unclear but may be due to statistical power or additional factors that contribute to a participant’s symptom assessment. Future adequately designed comparative
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combination nasal sprays.
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studies are needed to further evaluate the overall efficacy as well as onset of action of
GSP301 BID and QD were well tolerated with mild to moderate TEAEs that were
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distributed evenly between the treatments and did not lead to study discontinuation. Headache was the most commonly reported TEAE and occurred similarly across treatments (11.1% for
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GSP301 BID and Olopatadine; 8.3% for AzeFlu and placebo) except for a greater incidence in the GSP301 QD group (16.7%). In two pharmacokinetic studies of GSP301 in healthy participants,39,40 favorable safety and tolerability profiles were observed with low systemic exposure. Furthermore, in several large, natural allergen exposure studies in SAR, GSP301 QD
ACCEPTED MANUSCRIPT 15 or BID30-32 dosing were well tolerated with similar incidences of AEs to placebo or component monotherapies. This small proof-of-concept study was designed to test the efficacy and safety of the newly developed olopatadine/mometasone FDC nasal spray (GSP301). It should be noted that
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while environmental and dosing elements can be better controlled in an EEC study than in a natural allergen-exposure setting, there are still potentially confounding factors that cannot be completely controlled. Limitations of this study include participant-reported subjective symptom
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assessments without supporting objective measures, a potential placebo effect of nasal
irrigation,41 and a smaller sample size. Some of these limitations are inherent to any AR study employing subjective evaluations that require participants to optimally assess and report symptoms.
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In this EEC ragweed pollen study, treatment with either GSP301 BID or QD provided
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significant and clinically meaningful SAR nasal symptom improvement and significant ocular symptom improvement versus placebo. Both GSP301 regimens (BID and QD) were well
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tolerated with only mild–moderate adverse events reported. GSP301 BID treatment resulted in significant and clinically meaningful nasal symptom improvement versus placebo at 10 minutes
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and significance was maintained at 11 of the 12 subsequent time points over the 4-hour assessment. These results, taken together with those from GSP301 studies conducted in various
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pollen seasons,30-32 demonstrate that twice-daily dosing of GSP301 is an optimally efficacious and well-tolerated treatment option for the relief of nasal SAR symptoms.
ACCEPTED MANUSCRIPT 16 REFERENCES
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Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: Allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(1 Suppl):S1-43. Blackwell DL, Villarroel MA. Tables of summary health statistics for US adults: 2015 National Health Interview Survey. 2016; http://www.cdc.gov/nchs/nhis/SHS/tables.htm. Accessed October 26, 2017. Bloom B, Simpsom J. Tables of summary health statistics for US children: 2015 National Health Interview Survey. 2016; http://www.cdc.gov/nchs/nhis/SHS/tables.htm. Accessed October 26, 2017. Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc. 2010;31(5):375-380. Marple BF, Fornadley JA, Patel AA, et al. Keys to successful management of patients with allergic rhinitis: focus on patient confidence, compliance, and satisfaction. Otolaryngol Head Neck Surg. 2007;136(6 Suppl):S107-124. Meltzer EO. Allergic rhinitis: Burden of illness, quality of life, comorbidities, and control. Immunol Allergy Clin North Am. 2016;36(2):235-248. Prenner BM. A review of the clinical efficacy and safety of MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate, in clinical studies conducted during different allergy seasons in the US. J Asthma Allergy. 2016;9:135-143. Feng S, Fan Y, Liang Z, Ma R, Cao W. Concomitant corticosteroid nasal spray plus antihistamine (oral or local spray) for the symptomatic management of allergic rhinitis. Eur Arch Otorhinolaryngol. 2016;273(11):3477-3486. Harrow B, Sedaghat AR, Caldwell-Tarr A, Dufour R. A comparison of health care resource utilization and costs for patients with allergic rhinitis on single-product or freecombination therapy of intranasal steroids and intranasal antihistamines. J Manag Care Spec Pharm. 2016;22(12):1426-1436. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: A meta-analysis. Am J Med. 2007;120(8):713-719. van Galen KA, Nellen JF, Nieuwkerk PT. The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis. AIDS Res Treat. 2014;2014:967073. Kaliner MA, Oppenheimer J, Farrar JR. Comprehensive review of olopatadine: the molecule and its clinical entities. Allergy Asthma Proc. 2010;31(2):112-119. Fairchild CJ, Meltzer EO, Roland PS, Wells D, Drake M, Wall GM. Comprehensive report of the efficacy, safety, quality of life, and work impact of olopatadine 0.6% and olopatadine 0.4% treatment in patients with seasonal allergic rhinitis. Allergy Asthma Proc. 2007;28(6):716-723. Meltzer EO, Hampel FC, Ratner PH, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95(6):600-606. Brannan M, Seiberling M, Cutler D, Cuss F, Affirme M. Lack of systemic activity with intranasal mometasone furoate. J Allergy Clin Immunol. 1996;97:198. Hochhaus G. Pharmacokinetic/pharmacodynamic profile of mometasone furoate nasal spray: potential effects on clinical safety and efficacy. Clin Ther. 2008;30(1):1-13.
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Penagos M, Compalati E, Tarantini F, Baena-Cagnani CE, Passalacqua G, Canonica GW. Efficacy of mometasone furoate nasal spray in the treatment of allergic rhinitis. Metaanalysis of randomized, double-blind, placebo-controlled, clinical trials. Allergy. 2008;63(10):1280-1291. Passali D, Spinosi MC, Crisanti A, Bellussi LM. Mometasone furoate nasal spray: a systematic review. Multidiscip Respir Med. 2016;11:18. Shah SR, Nayak A, Ratner P, Roland P, Michael Wall G. Effects of olopatadine hydrochloride nasal spray 0.6% in the treatment of seasonal allergic rhinitis: a phase III, multicenter, randomized, double-blind, active- and placebo-controlled study in adolescents and adults. Clin Ther. 2009;31(1):99-107. Salapatek AM, Patel P, Gopalan G, Varghese ST. Mometasone furoate nasal spray provides early, continuing relief of nasal congestion and improves nasal patency in allergic patients. Am J Rhinol Allergy. 2010;24(6):433-438. Patel D, Garadi R, Brubaker M, et al. Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28(5):592-599. Patel P, Roland PS, Marple BF, et al. An assessment of the onset and duration of action of olopatadine nasal spray. Otolaryngol Head Neck Surg. 2007;137(6):918-924. Patanase® (olopatadine hydrochloride nasal spray). US prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2015. Dymista® (azelastine hydrochloride and fluticasone propionate nasal spray). US prescribing information. Meda Pharmaceuticals Inc, Somerset, NJ; 2015. Pfaar O, Calderon MA, Andrews CP, et al. Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future - an EAACI Position Paper. Allergy. 2017;72(7):1035-1042. Barnes ML, Vaidyanathan S, Williamson PA, Lipworth BJ. The minimal clinically important difference in allergic rhinitis. Clin Exp Allergy. 2010;40(2):242-250. Ratner PH, Hampel F, Van Bavel J, et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100(1):74-81. Hampel FC, Ratner PH, Van Bavel J, et al. Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device. Ann Allergy Asthma Immunol. 2010;105(2):168-173. Meltzer EO, LaForce C, Ratner P, Price D, Ginsberg D, Carr W. MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial of efficacy and safety. Allergy Asthma Proc. 2012;33(4):324-332. Andrews CP, Mohar D, Agarwal P, Salhi Y, Tantry SK. Efficacy and safety of once-daily and twice-daily olopatadine/mometasone nasal spray treatment in seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American College of Allergy, Asthma, and Immunology; October 26-30, 2017; Boston, MA. Ratner P, Hampel F, Breazna A, Caracta C, Tantry SK. Efficacy and safety of olopatadine/mometasone combination nasal spray for the treatment of seasonal allergic rhinits. Poster presented at: 75th annual meeting of the American College of Allergy, Asthma, and Immunology; October 26-30, 2017; Boston, MA.
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Hampel F, Pedinoff A, Jacobs R, Breazna A, Caracta C, Tantry S. Efficacy and safety of olopatadine/mometasone combination nasal spray in patients with seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American Academy of Allergy, Asthma, and Immunology; March 2-5, 2018; Orlando, FL. Berman G, Amar NJ, LaForce CF, Breazna A, Caracta C, Tantry SK. Rapid onset of action on nasal symptoms and ocular symptom improvement with olopatadine/mometasone combination nasal spray in patients with seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American Academy of Allergy, Asthma, and Immunology; March 2-5, 2018; Orlando, FL. Patel P, D'Andrea C, Sacks HJ. Onset of action of azelastine nasal spray compared with mometasone nasal spray and placebo in subjects with seasonal allergic rhinitis evaluated in an environmental exposure chamber. Am J Rhinol. 2007;21(4):499-503. Meltzer EO, Rickard KA, Westlund RE, Cook CK. Onset of therapeutic effect of fluticasone propionate aqueous nasal spray. Ann Allergy Asthma Immunol. 2001;86(3):286-291. Couroux P, Kunjibettu S, Hall N, Wingertzahn MA. Onset of action of ciclesonide once daily in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2009;102(1):62-68. Nasonex® (mometasone furoate monohydrate nasal spray). US prescribing information. Schering-Plough Corporation, Kenilworth, NJ; 2013. Bousquet J, Meltzer EO, Couroux P, et al. Onset of Action of the Fixed Combination Intranasal Azelastine-Fluticasone Propionate in an Allergen Exposure Chamber. J Allergy Clin Immunol Pract. 2018. Patel P, Salapatek AM, Talluri RS, Tantry SK. Pharmacokinetics of intranasal mometasone in the fixed-dose combination GSP301 versus two monotherapy intranasal mometasone formulations. Allergy Asthma Proc. 2018;39(3):232-239. Patel P, Salapatek AM, Talluri RS, Tantry SK. Pharmacokinetics of intranasal olopatadine in the fixed-dose combination GSP301 versus two monotherapy intranasal olopatadine formulations. Allergy Asthma Proc. 2018;39(3):224-231. Head K, Snidvongs K, Glew S, et al. Saline irrigation for allergic rhinitis. Cochrane Database Syst Rev. 2018(6).
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Figure 1. Study Design
During at-home dosing for 12 days, participants self-administered study drug approximately 12
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hours apart, based on treatment, without symptom assessment.
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Visit 2 EEC occurred approximately 24 hours before the first dose of study treatment; Visit 3 EEC was 10 hours, with 6 hours spent in the EEC immediately before the first dose of study
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treatment taken at 12 PM followed by an additional 4 hours after the first dose; Visit 4 EEC
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occurred approximately 1 hour after the morning (12 PM) dose on Day 14; Visit 5 EEC occurred approximately 6 hours after the last dose of study treatment taken at 12 AM on Day 14. The
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duration of EEC Visits 2, 4, and 5 was approximately 6 hours each. EC, exclusion criteria; EEC, environmental exposure chamber; IC, inclusion criteria.
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Figure 2. iTNSS Mean (SE) Change from Baseline (Visit 3) to End of Treatment (Visit 5) for GSP301 BID and QD Versus Placebo (ITT Population)
665 μg/mometasone 50 μg.
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine
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BID, twice-daily dosing; iTNSS, instantaneous Total Nasal Symptom Score; ITT, intention-to-
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treat; QD, once-daily dosing; SE, standard error.
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Figure 3. LS Mean (SE) of
Average iTNSS for GSP301 BID Versus Placebo (ITT Population) GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg.
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treat; LS, least squares; SE, standard error.
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Olopatadine (n=36)
Placebo (n=36)
41.6 ± 11.4
42.1 ± 12.5
16 (44.4) 20 (55.6) 76.2 ± 17.2
16 (44.4) 20 (55.6) 76.0 ± 16.5
17 (47.2) 12 (33.3) 6 (16.7) 1 (2.8)
18 (50.0) 11 (30.6) 7 (19.4) 0 (0)
33 (91.7)
35 (97.2)
3 (8.3) 8.3 ± 2.1 4.2 ± 1.9
1 (2.8) 7.6 ± 2.2 4.3 ± 1.8
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Table 1. Demographics and Baseline Characteristics (Safety Population) GSP301 GSP301 BID AzeFlu QD (n=36) (n=36) (n=36) Age, mean ± SD, y 38.3 ± 10.8 44.9 ± 11.8 41.1 ± 10.0 Sex, n (%) Male 22 (61.1) 18 (50.0) 19 (52.8) Female 14 (38.9) 18 (50.0) 17 (47.2) Weight, mean ± SD, kg 82.0 ± 19.6 81.7 ± 14.2 83.3 ± 17.8 Race, n (%) White 20 (55.6) 14 (38.9) 20 (55.6) Black 9 (25.0) 13 (36.1) 13 (36.1) Asian 5 (13.9) 8 (22.2) 2 (5.6) Othera 2 (5.6) 1 (2.8) 1 (2.8) Ethnicity, n (%) Non-Hispanic or 32 (88.9) 31 (86.1) 30 (83.3) Latino Hispanic or Latino 4 (11.1) 5 (13.9) 6 (16.7) iTNSS, mean ± SDb 8.1 ± 2.3 8.2 ± 2.1 8.7 ± 2.5 iTOSS, mean ± SDb 4.3 ± 1.9 4.5 ± 2.3 4.8 ± 2.1
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. a Includes participants of mixed race and those that did not identify with the other mentioned race categories. b ITT population. BID, twice-daily dosing; FDA, Food and Drug Administration; iTNSS, instantaneous Total Nasal Symptom Score; iTOSS, instantaneous Total Ocular Symptom Score; ITT, intention-to-treat; QD, once-daily dosing; SD, standard deviation.
ACCEPTED MANUSCRIPT 23 Table 2. LS Mean Difference in Average iTNSS for Active Treatments Versus Placebo (ITT Population) Treatment Groups (T1 vs T2) n1, n2 LSMD 95% CI GSP301 BID versus Placebo 36, 35 -3.60 (-4.89, -2.30) GSP301 QD versus Placebo 36, 35 -3.05 (-4.35, -1.76) AzeFlu versus Placebo 34, 35 -2.83 (-4.05, -1.61) Olopatadine versus Placebo 36, 35 -0.81 (-2.00, 0.38)
P value <0.0001 <0.0001 <0.0001 0.179
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. BID, twice-daily dosing; CI, confidence interval; FDA, Food and Drug Administration; FDC, fixed-dose combination; iTNSS, instantaneous Total Nasal Symptom Score; ITT, intention-to-treat; LS, least squares; LSMD, least squares mean difference; QD, once-daily dosing; SE, standard error.
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AzeFlu (n=36)
Olopatadine (n=36)
Placebo (n=36)
9 (25.0)
8 (22.2)
6 (16.7)
3 (8.3) 1 (2.8) 2 (5.6) 0 (0) 5 (13.9) 0 (0) 0 (0)
4 (11.1) 1 (2.8) 2 (5.6) 2 (5.6) 6 (16.7) 0 (0) 0 (0)
3 (8.3) 0 (0) 0 (0) 0 (0) 3 (8.3) 0 (0) 0 (0)
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Table 3. Summary of Adverse Events (Safety Population) GSP301 GSP301 BID QD n (%) (n=36) (n=36) Participants reporting ≥1 8 (22.2) 11 (30.6) TEAE TEAEsa Headache 4 (11.1) 6 (16.7) Dysgeusia 2 (5.6) 1 (2.8) Epistaxis 0 (0) 0 (0) Rash 0 (0) 0 (0) Treatment-related TEAEs 7 (19.4) 5 (13.9) TEAEs leading to withdrawal 0 (0) 0 (0) SAEs 0 (0) 0 (0)
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. a Occurring in ≥2% of participants in any treatment group. BID, twice-daily; FDA, Food and Drug Administration; QD, once-daily; SAE, serious adverse event; TEAE, treatmentemergent adverse event.
Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study Piyush Patel MD , Anne Marie Salapatek PhD , Sudeesh K. Tantry PhD PII: DOI: Reference:
S1081-1206(18)31308-5 https://doi.org/10.1016/j.anai.2018.10.011 ANAI 2722
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
29 May 2018 1 October 2018 9 October 2018
Please cite this article as: Piyush Patel MD , Anne Marie Salapatek PhD , Sudeesh K. Tantry PhD , Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study, Annals of Allergy, Asthma Immunology (2018), doi: https://doi.org/10.1016/j.anai.2018.10.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study
Piyush Patel, MD1 Anne Marie Salapatek, PhD1 Sudeesh K. Tantry, PhD2 Inflamax Research Inc, Mississauga, Ontario, CA; 2Glenmark Pharmaceuticals, Paramus, NJ,
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Corresponding Author: Piyush Patel, MD 1310 Fewster Drive Mississauga, ON, L4W 1A4
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Tel: 905-282-6310 Fax: 905-206-2690
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Email: [email protected]
Conflicts of Interest: Piyush Patel, MD is the CEO and Principal Scientist at Inflamax Research
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(Mississauga, ON, CA, a member of Cliantha Research) and was the site principal investigator on this trial funded by Glenmark Pharmaceuticals. Anne Marie Salapatek, PhD is the Executive
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Vice President and Chief Science Officer for Inflamax Research (Mississauga, ON, CA, a member of Cliantha Research) and was involved in the design and conduct of this study funded by Glenmark Pharmaceuticals. Sudeesh K. Tantry is an employee of Glenmark Pharmaceuticals. Funding: Glenmark Specialty SA
ACCEPTED MANUSCRIPT 2 Acknowledgments Assistance with medical writing, editing, and formatting of the manuscript for submission was provided by Lynn M. Anderson, PhD of Prescott Medical Communications Group (Chicago, IL)
Trial Registration: ClinicalTrials.gov, NCT03444506
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and funded by Glenmark Specialty SA.
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Abstract: BACKGROUND: GSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate intended for seasonal allergic rhinitis (SAR) treatment. OBJECTIVE: Efficacy and safety of GSP301 once-daily (QD) or twice-daily (BID) were evaluated in a ragweed pollen Environmental Exposure Chamber (EEC). METHODS: In this randomized, double-blind, double-dummy study, adults (18-65 years) with SAR were equally randomized to GSP301 BID (olopatadine 665μg/mometasone 25μg), GSP301 QD (olopatadine 665μg/mometasone 50μg), AzeFlu (FDA-approved azelastine 137μg/fluticasone 50μg BID), Olopatadine (FDA-approved formulation 665μg BID), or placebo (BID). During two visits (baseline and end of 14-day treatment), participants assessed SAR symptoms at specified time points. The primary endpoint—mean change from baseline in instantaneous Total Nasal Symptom Score (iTNSS) for GSP301 BID or QD versus placebo—was analyzed by ANCOVA. Onset of action, ocular symptoms, and adverse events (AEs) were assessed. RESULTS: A total of 180 participants were randomized. Treatment with GSP301 BID or QD provided statistically significant improvements in iTNSS versus placebo (least squares mean difference [95% CI] GSP301 BID: -3.60 [-4.89, -2.30]; QD: -3.05 [-4.35, -1.76]; P<0.0001, both). Significant improvements in iTNSS with GSP301 BID occurred by 10 minutes post-dose (1.26 [-2.30, -0.21], P=0.019) and were maintained at all later time points except one (2.5 hours). Treatment-emergent AEs occurred in 22.2%, 30.6%, 25.0%, 22.2%, and 16.7% of participants in GSP301 BID, GSP301 QD, AzeFlu, Olopatadine, and placebo groups, respectively. CONCLUSION: In an EEC model, GSP301 BID and QD treatments were well tolerated and provided statistically significant and clinically meaningful SAR symptom improvement versus placebo.
Keywords (up to 12; up to 5 phrases): combination nasal spray; seasonal allergic rhinitis; olopatadine; mometasone; environmental exposure chamber; ragweed pollen; onset of action
ACCEPTED MANUSCRIPT 3 INTRODUCTION Allergic rhinitis (AR) is an inflammatory disease1 affecting 20 million adults2 and 6 million children3 in the US. The economic burden of AR is substantial with total annual expenditures in 2005 estimated at $11.2 billion (USD), driven primarily by prescription drug costs.4 Further
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adding to this burden, AR symptoms can negatively impact quality of life through decreased work/school productivity, disturbed sleep, fatigue, irritability, and depression.5,6
Although pharmacological options to treat AR are available, symptom control is
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inadequate for many patients. Of patients who reported using at least one prescription allergy treatment, 47% were using two or more agents, and many frequently supplemented with nonprescription allergy treatments.5 Since nasal symptoms (congestion, rhinorrhea, itching and sneezing) and non-nasal symptoms (itching/burning, tearing/watering, and redness of eyes;
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itching of ears/palate) can occur within minutes of allergen exposure, medications that provide both immediate and sustained relief with minimal side effects are essential for effective disease
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management.5 Combining a fast-acting intranasal antihistamine with a long-acting intranasal
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corticosteroid may be more effective in controlling AR symptoms than monotherapy treatment.7,8 Using a single-device combination treatment in place of multiple monotherapy agents may also
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reduce healthcare costs9 (depending on local pricing) and improve treatment adherence.10,11
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GSP301 is a fixed-dose combination (FDC) of the antihistamine olopatadine hydrochloride (HCl) and the corticosteroid mometasone furoate developed as a single nasal spray for the treatment of seasonal AR (SAR) symptoms. Olopatadine is a well-tolerated, highly selective histamine H1-receptor antagonist with anti-inflammatory properties12 that, when applied intranasally, reduces itchy/runny nose and sneezing.13,14 The intranasal corticosteroid mometasone effectively reduces SAR symptoms of nasal itching and congestion, sneezing, and
ACCEPTED MANUSCRIPT 4 rhinorrhea by inhibiting the release of inflammatory mediators and has a well-documented safety profile with minimal systemic effects.15-18 The efficacy and safety of US Food and Drug Administration (FDA)-approved olopatadine HCl (Olopatadine) and mometasone furoate monotherapy nasal sprays have been demonstrated in natural allergen-exposure studies13,14,17,19
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as well as in studies using an Environmental Exposure Chamber (EEC).20-22
The objective of this study was to evaluate the efficacy and safety of GSP301 once-daily (QD) or twice-daily (BID) treatments versus placebo and two FDA-approved nasal sprays,
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Olopatadine23 and AzeFlu (an FDC containing the antihistamine azelastine HCl and the
glucocorticoid fluticasone propionate),24 in participants with SAR using a ragweed pollen EEC model. The advantage of an EEC study over a natural allergen-exposure study is that participants with AR can be exposed to an allergen of choice, allowing for consistent allergen level exposure
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over the entire course of the study, as well as continual monitoring of participant compliance with procedures and treatments. An EEC study controls the inherent variability that is present in
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natural allergen-exposure studies.25
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METHODS
This study (NCT03444506) was conducted in accordance with the Declaration of Helsinki Good
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Clinical Practice (GCP) according to International Conference on Harmonization (ICH)
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guidelines. The protocol received ethical clearance from the Institutional Review Board Services (Aurora, Ontario, Canada) and was carried out according to applicable local regulatory requirements. All participants provided written informed consent.
ACCEPTED MANUSCRIPT 5 Study Design and Assessments This was a randomized, single-site, double-blind, double-dummy, placebo-controlled, parallelgroup proof-of-concept study conducted outside of the ragweed pollen season (January/February). The study consisted of a screening visit, five EEC visits (priming, pre-dose,
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post-dose, and two post-12-day at-home dosing), and 12 days of at-home dosing (Figure 1). Participants were dosed for a total of 14 days. Exposure to airborne ragweed pollen (3500 ± 500 particles/m3) occurred for 6 hours in an EEC at visits 2 (pre-treatment priming), 3, 4 (post-
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treatment priming), and 5. At visit 3, participants were in the EEC for 6 hours in order to develop SAR symptoms, upon which eligible participants were equally randomized to one of the following treatments: GSP301 BID (sponsor olopatadine 665 μg/sponsor mometasone 25 μg); GSP301 QD (sponsor olopatadine 665 μg/sponsor mometasone 50 μg); AzeFlu BID (azelastine
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137 μg/fluticasone 50 μg; FDA-approved formulation); Olopatadine BID (665 μg; FDAapproved formulation); or placebo BID (based on the GSP301 formulation). Participants were
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provided with 4 nasal spray bottles (2 for AM dosing and 2 for PM dosing) and self-administered
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1 spray/nostril from each bottle every day. For AzeFlu dosing (1 spray/nostril vs 2 sprays/nostril), 2 bottles of AzeFlu (1 for AM and 1 for PM) and 2 bottles of placebo (1 for AM
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and 1 for PM) were provided to maintain blinding. Participants administered their first treatment under observation at the research site for 2 days. Thereafter, double-blinded treatments were self-
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administered over 12 days at home, without symptom assessment. To evaluate efficacy, SAR nasal and ocular symptoms were assessed by participants in the EEC during four clinic visits (visits 2, 3, 4 and 5) at prespecified time points. Participants rated how they felt at the time of the assessment (ie, instantaneous symptoms) using the instantaneous Total Nasal Symptom Score (iTNSS) and the instantaneous Total Ocular Symptom Scores (iTOSS) in
ACCEPTED MANUSCRIPT 6 an electronic dairy (Figure 1). Symptoms were rated on a scale of 0 (absent) to 3 (severe; see supplemental Table S1). Nasal symptoms included congestion, rhinorrhea, itching and sneezing; ocular symptoms included itching/burning, tearing/watering, and redness of eyes.
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Participants Eligible participants included adults aged 18 to 65 years with a clinical history of SAR for at least 2 years for ragweed pollen who had a positive skin prick test for ragweed (wheal diameter ≥3 mm than negative control). Participants were not required to be mono-sensitized to ragweed
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pollen. At the screening/priming visit (visit 2), participants must have met a minimum iTNSS ≥6 out of 12 (including a score of ≥2 for nasal congestion) on ≥2 consecutive diary entries; at the randomization visit (visit 3), participants must have met a minimum iTNSS ≥6 out of 12 (including a score of ≥2 for nasal congestion) on at least 1 diary entry in the first 6 hours of the
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EEC session.
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Key exclusion criteria consisted of: known history of acute or significant chronic sinusitis, chronic purulent post-nasal drip, rhinitis medicamentosa, nasal surgery, or nasal
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structural abnormalities including ulceration, mucosal erosion, large polyps or marked septal deviations that significantly interfered with nasal air flow. Participants could not be dependent on
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nasal, oral, or ocular decongestants, nasal topical antihistamines or nasal steroids or use
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inhaled/systemic corticosteroids chronically (excluding ≤8 puffs/day of inhaled short-acting βagonists). Furthermore, participants could not have a history of seasonal asthma during ragweed season or a known history of hypothalamic-pituitary-adrenal axis disease or dysfunction. Use of the following medications was not permitted 5 days prior to initial dosing: antihistamines, anticholinergics, or products containing ephedrine, pseudoephedrine or decongestants. The following medications were not permitted for up to 30 days prior to dosing:
ACCEPTED MANUSCRIPT 7 ocular, intranasal, or systemic corticosteroids (7, 14, or 30 days prior, respectively); leukotriene inhibitors, cromolyn, or systemic antibiotics (14 days prior); immunosuppressants/modulators (30 days prior). Immunoglobulin E antagonists could not be used for 120 days prior to initial dosing. Use of intranasal therapies, topical corticosteroids, ophthalmic drops, clinical trial drugs,
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radiation therapy, injectable immunotherapy, rescue medications for AR control (ie,
oral/intranasal antihistamines or anticholinergics, intranasal corticosteroids, decongestants, or ephedrine/pseudoephedrine-containing products), or exposure to cytochrome P450 3A4
inhibiting or inducing drugs (eg, carbamazepine, dexamethasone, phenytoin, rifabutin, rifampin,
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pioglitazone) were not permitted at any time during the study. Consumption of food or drink containing grapefruit, orange, apple, mustard green family vegetables, alcohol, and charbroiled meat was not permitted during study participation.
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Endpoints
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The primary endpoint was the mean change from baseline (visit 3) to end of treatment (visit 4) in post-dose iTNSS for GSP301 BID and QD versus placebo. Secondary endpoints included mean
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change from baseline to end of treatment in post-dose iTNSS for: GSP301 BID and QD versus AzeFlu and versus Olopatadine; AzeFlu and Olopatadine compared with placebo.
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Additional secondary endpoints included evaluation of onset of action and ocular
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symptom assessment. Onset of action for each treatment was determined by the mean change from baseline in iTNSS versus placebo at 5, 10, 15, 20, 25, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, and 4 hours after the first dose of study treatment (in the 4 hours post-dose at visit 3). Ocular symptoms (itching, tearing/watery eyes, redness) were assessed through mean change from baseline (visit 3) to end of treatment (visit 5) in post-dose iTOSS for: GSP301 BID and QD versus placebo; GSP301 BID versus AzeFlu and Olopatadine; and GSP301 QD versus AzeFlu
ACCEPTED MANUSCRIPT 8 and Olopatadine. Safety was monitored through ear, nose and throat examinations, as well as adverse event (AE) reporting. Statistical Analysis
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Efficacy analyses were based on the intention-to-treat (ITT) population, defined as all randomized participants who received ≥1 dose of study drug and completed ≥1 efficacy
assessment during treatment. Safety assessments were based on the safety population, which included all participants who received ≥1 dose of study drug. Baseline demographic variables
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and AEs were summarized by treatment group using descriptive statistics. Change from baseline in mean post-treatment iTNSS was examined by analysis of covariance (ANCOVA) with baseline as a covariate and treatment as a fixed effect. Baseline was defined as the average of symptom scores over 6 hours in the EEC at visit 3 immediately prior to the first dose (day 1). A
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treatment difference that reached P<0.05 was considered statistically significant (referred to as
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“significant”) and a treatment difference of at least 0.23 units on TNSS was considered clinically meaningful using direct anchor-based methodology (defined as the minimal clinically important
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difference).26 Onset of action was defined as the first of two consecutive time points after initiation of treatment when the drug demonstrated a significant difference in iTNSS compared
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to the placebo as long as the significant difference was sustained. Onset was analyzed using ANCOVA with baseline as a covariate and treatment as a fixed effect. Baseline was
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characterized as the average of the last two predose time points at visit 3 (-1.0 h and -0.5 h). Change from baseline in mean post-treatment iTOSS was also analyzed using ANCOVA, with baseline as a covariate and treatment as a fixed effect. All tests were two-sided using a significance level of 5% and all analyses were conducted using SAS® (v 9.2 or higher). Sample Size
ACCEPTED MANUSCRIPT 9 To detect a between-treatment difference of 1.65 units in the mean change from baseline in iTNSS for the primary endpoint (GSP301 versus placebo; over 6 hours in the EEC) at visit 5 with a standard deviation of 2.24 units and with a power of 0.80, at least 30 evaluable participants needed to be randomized to each group (150 participants total; based on unpublished
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data on file). A total of 180 participants were enrolled, assuming a drop-out rate of 15%. RESULTS Participants
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A total of 180 participants were randomized (n=36 in each treatment group), with mean ages ranging from 38.3 to 44.9 years across treatments (Table 1). At baseline, participants had moderate to severe SAR symptoms, with mean iTNSS ranging from 7.6 to 8.7 and mean iTOSS ranging from 4.2 to 4.8 (Table 1). One participant in the GSP301 QD group discontinued the
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study due to a family emergency and 3 participants (2 in the AzeFlu group and 1 in the placebo
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group) discontinued due to failure to follow study procedures. Efficacy
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iTNSS
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For the primary endpoint, treatment with GSP301 BID or QD showed statistically significant and clinically meaningful improvements in iTNSS versus placebo (P<0.0001, both; Table 2). These
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improvements were sustained during the entire 6-hour post-treatment EEC session (Figure 2). For the secondary endpoints, significant improvement in iTNSS occurred with AzeFlu compared with placebo (P<0.0001; Table 2); Olopatadine versus placebo yielded clinically meaningful, but not statistically significant, improvement in iTNSS (P=0.18; Table 2). GSP301 BID and QD showed significant and clinically meaningful improvements in iTNSS versus Olopatadine
ACCEPTED MANUSCRIPT 10 treatment (LSMD [95% CI] GSP301 BID: -2.94 [-4.23, -1.64], P<0.0001; QD: -2.39 [-3.69, 1.10], P=0.0004). Similar clinically meaningful improvements were observed with GSP301 BID and QD compared with AzeFlu, but these did not reach statistical significance (GSP301 BID: 1.09 [-2.46, 0.28], P=0.118; QD: -0.53 [-1.90, 0.83], P=0.441).
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Onset of Action
A significant difference in change from baseline in iTNSS occurred at 10 minutes post-dose for GSP301 BID versus placebo (LSMD [95% CI]: -1.26 [-2.30, -0.21], P=0.019), and was
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maintained at 11 out of the 12 subsequent time points (P<0.05, all); the change from baseline in iTNSS did not reach statistical significance only at the 2.5-hour assessment (P=0.065; Figure 3). The improvements with GSP301 BID were clinically meaningful at all time points. There were no statistically significant differences in change from baseline in iTNSS between the other active
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treatments (GSP301 QD, AzeFlu, and Olopatadine) and placebo at any time point, with the
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exception of GSP301 QD at 3 and 4 hours post-dose (P=0.04 and P=0.01, respectively; data not shown) and Olopatadine at 10 minutes post-dose only (P=0.01; data not shown).
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iTOSS
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Treatment with GSP301 BID or QD resulted in significant ocular symptom (iTOSS) improvements versus placebo (LSMD [95% CI] BID: -1.64 [-2.60, -0.68], P<0.0001; QD: -1.20
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[-2.15, -0.24], P=0.015). GSP301 BID significantly improved ocular symptoms versus Olopatadine (P=0.04) but not versus AzeFlu (data not shown). Safety
The percentage of participants reporting ≥1 treatment emergent AE (TEAE) was generally comparable among the treatment groups, with a slightly greater percentage in the GSP301 QD
ACCEPTED MANUSCRIPT 11 group (Table 3). Headache and dysgeusia were the most frequently reported TEAEs and occurred similarly across treatments except for a greater percentage in the GSP301 QD (headache) and BID (dysgeusia) groups versus placebo. All TEAEs were mild to moderate and none led to study discontinuation. No serious adverse events (SAEs) or deaths were reported.
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DISCUSSION
Developing effective treatments for AR is important as symptom control is often inadequate, with many patients requiring more than one prescription medication or additional treatments.5,6
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Studies have shown that combining a nasal spray antihistamine and corticosteroid may be more effective in reducing AR symptoms than monotherapy alone.27-31 Furthermore, combined (FDC) treatment in a single-device may reduce medical and pharmacy costs (depending on local pricing) compared with using multiple monotherapies.9
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Results from this proof-of-concept study demonstrated that the FDC containing
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mometasone furoate and olopatadine hydrochloride in a single nasal spray (GSP301) delivered BID or QD provides significant and clinically meaningful26 nasal symptom improvement versus
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placebo in participants with moderate to severe SAR exposed to ragweed in an EEC. Statistically significant improvements with GSP301 BID were rapid, occurring within 10 minutes of dosing.
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Rapid significant symptom relief was maintained at 11 of the 12 subsequent time points during
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the 4-hour assessment period; the assessment at 2.5 hours did not reach statistical significance (P=0.06). GSP301 BID and QD also significantly improved ocular symptoms compared with placebo.
These results complement those observed in later natural allergen exposure SAR studies with GSP301 where dosing BID30-32 or QD30 provided significant, clinically meaningful,26 and sustained nasal symptom improvements. Furthermore, the results from a large, phase 2 natural
ACCEPTED MANUSCRIPT 12 allergen exposure study demonstrated that GSP301 BID was the optimally safe and efficacious dosage regimen.30 GSP301 BID also demonstrated a rapid onset of action (15 minutes – first time point tested post-dose) in the natural allergen studies that was maintained at all subsequent time points assessed.30-32 Furthermore, GSP301 BID provided significant improvements in ocular
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symptoms in two large SAR studies conducted in different pollen seasons.33 Overall, the results from the current study combined with those of natural-allergen exposure studies demonstrate that GSP301 provides rapid, clinically meaningful improvements in SAR nasal symptoms as well as significant ocular symptom improvements in multiple pollen seasons and under different
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exposure conditions (ie, EEC versus natural allergen).
In addition to demonstrating nasal symptom improvement over placebo, GSP301 BID and QD provided clinically meaningful26 nasal symptom improvement versus the commercially
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available AzeFlu and Olopatadine treatments, but only comparisons with Olopatadine were statistically significant. As expected, AzeFlu and Olopatadine both demonstrated clinically
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meaningful26 improvements in nasal symptoms versus placebo, though the comparison of
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Olopatadine versus placebo did not reach statistical significance. The reason for the nonsignificance in some of these comparisons is unclear. As noted earlier, the current study was
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powered at 80% and a larger sample size may be necessary to assess the efficacy of all treatment comparisons. It should also be noted that the placebo formulation used in this study was based on
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the GSP301 vehicle rather than the reference treatments. However, in later adequately powered phase 2 and 3 natural allergen-exposure SAR studies, an olopatadine formulation (BID) made with the GSP301 vehicle (sponsor olopatadine formulation) provided significant and clinically meaningful improvements in nasal symptoms versus placebo.30,31
ACCEPTED MANUSCRIPT 13 The desire among AR patients for rapid and long-lasting symptom relief5 can be achieved by combining an antihistamine and a corticosteroid into a single intranasal formulation. Indeed, intranasal formulations of antihistamines and corticosteroids are efficacious monotherapies that differ in onset of action, with antihistamines providing immediate but short-term symptom relief
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(15−30 minutes) and corticosteroids providing sustained symptom relief with a longer onset of action (3−36 hours).1 Combining these monotherapies into one treatment allows for both
immediate and sustained relief. For example, the FDA-approved combination treatment AzeFlu has an onset of action of 30 minutes29 whereas the individual monotherapies, azelastine and
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fluticasone, have onsets of 15 minutes34 and 12 hours,35 respectively.
In the current study, onset of action was defined as the first of two consecutive time points after initiation of treatment at which the drug demonstrated a significant reduction in
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iTNSS compared to placebo that was sustained. GSP301 BID treatment resulted in significant and clinically meaningful symptom improvement versus placebo at 10 minutes and significance
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was maintained at 11 of the 12 subsequent time points over the 4-hour assessment. Historically,
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the interpretation has been that onset of action can still be defined even if the treatment difference does not reach statistical significance at all time points during the time course as long
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as the difference is considered sustained.22,36 For GSP301 BID, the first of two consecutive time points that were significantly different from placebo occurred at 10 minutes, which is
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considerably shorter than the onset of action reported in studies of the component monotherapies: olopatadine monotherapy has been shown to have an onset of action of 30 minutes21-23 while onset for mometasone ranges from 150 minutes (EEC study)21 to 11 hours (natural allergen and EEC studies).37 In two large, phase 3 natural allergen exposure SAR studies of GSP301 BID, onset of action was observed at the earliest time point assessed (15 minutes
ACCEPTED MANUSCRIPT 14 after the first dose) and was sustained at all later time points of onset evaluation session.33 When combined with the findings from the current study, there is evidence that GSP301 has a shorter onset of action than reported for either of the component monotherapies. In this study, significant and clinically meaningful iTNSS improvements seen at 10
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minutes with GSP301 BID were shorter than the onset of action reported for the marketed
combination nasal spray, azelastine hydrochloride/fluticasone propionate (AzeFlu) in a natural allergen exposure study (10 minutes for GSP301 versus 30 minutes for AzeFlu). However, in a
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specifically designed EEC study, TNSS for AzeFlu versus placebo was significantly reduced to 5 minutes.38 Onset of action for GSP301 QD, AzeFlu and Olopatadine were not determined in the current study, however, as significant differences in iTNSS change from baseline between these treatments and placebo were not observed at any two consecutive time points. The reason for
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these varying results is unclear but may be due to statistical power or additional factors that contribute to a participant’s symptom assessment. Future adequately designed comparative
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combination nasal sprays.
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studies are needed to further evaluate the overall efficacy as well as onset of action of
GSP301 BID and QD were well tolerated with mild to moderate TEAEs that were
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distributed evenly between the treatments and did not lead to study discontinuation. Headache was the most commonly reported TEAE and occurred similarly across treatments (11.1% for
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GSP301 BID and Olopatadine; 8.3% for AzeFlu and placebo) except for a greater incidence in the GSP301 QD group (16.7%). In two pharmacokinetic studies of GSP301 in healthy participants,39,40 favorable safety and tolerability profiles were observed with low systemic exposure. Furthermore, in several large, natural allergen exposure studies in SAR, GSP301 QD
ACCEPTED MANUSCRIPT 15 or BID30-32 dosing were well tolerated with similar incidences of AEs to placebo or component monotherapies. This small proof-of-concept study was designed to test the efficacy and safety of the newly developed olopatadine/mometasone FDC nasal spray (GSP301). It should be noted that
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while environmental and dosing elements can be better controlled in an EEC study than in a natural allergen-exposure setting, there are still potentially confounding factors that cannot be completely controlled. Limitations of this study include participant-reported subjective symptom
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assessments without supporting objective measures, a potential placebo effect of nasal
irrigation,41 and a smaller sample size. Some of these limitations are inherent to any AR study employing subjective evaluations that require participants to optimally assess and report symptoms.
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In this EEC ragweed pollen study, treatment with either GSP301 BID or QD provided
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significant and clinically meaningful SAR nasal symptom improvement and significant ocular symptom improvement versus placebo. Both GSP301 regimens (BID and QD) were well
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tolerated with only mild–moderate adverse events reported. GSP301 BID treatment resulted in significant and clinically meaningful nasal symptom improvement versus placebo at 10 minutes
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and significance was maintained at 11 of the 12 subsequent time points over the 4-hour assessment. These results, taken together with those from GSP301 studies conducted in various
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pollen seasons,30-32 demonstrate that twice-daily dosing of GSP301 is an optimally efficacious and well-tolerated treatment option for the relief of nasal SAR symptoms.
ACCEPTED MANUSCRIPT 16 REFERENCES
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Penagos M, Compalati E, Tarantini F, Baena-Cagnani CE, Passalacqua G, Canonica GW. Efficacy of mometasone furoate nasal spray in the treatment of allergic rhinitis. Metaanalysis of randomized, double-blind, placebo-controlled, clinical trials. Allergy. 2008;63(10):1280-1291. Passali D, Spinosi MC, Crisanti A, Bellussi LM. Mometasone furoate nasal spray: a systematic review. Multidiscip Respir Med. 2016;11:18. Shah SR, Nayak A, Ratner P, Roland P, Michael Wall G. Effects of olopatadine hydrochloride nasal spray 0.6% in the treatment of seasonal allergic rhinitis: a phase III, multicenter, randomized, double-blind, active- and placebo-controlled study in adolescents and adults. Clin Ther. 2009;31(1):99-107. Salapatek AM, Patel P, Gopalan G, Varghese ST. Mometasone furoate nasal spray provides early, continuing relief of nasal congestion and improves nasal patency in allergic patients. Am J Rhinol Allergy. 2010;24(6):433-438. Patel D, Garadi R, Brubaker M, et al. Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28(5):592-599. Patel P, Roland PS, Marple BF, et al. An assessment of the onset and duration of action of olopatadine nasal spray. Otolaryngol Head Neck Surg. 2007;137(6):918-924. Patanase® (olopatadine hydrochloride nasal spray). US prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2015. Dymista® (azelastine hydrochloride and fluticasone propionate nasal spray). US prescribing information. Meda Pharmaceuticals Inc, Somerset, NJ; 2015. Pfaar O, Calderon MA, Andrews CP, et al. Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future - an EAACI Position Paper. Allergy. 2017;72(7):1035-1042. Barnes ML, Vaidyanathan S, Williamson PA, Lipworth BJ. The minimal clinically important difference in allergic rhinitis. Clin Exp Allergy. 2010;40(2):242-250. Ratner PH, Hampel F, Van Bavel J, et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100(1):74-81. Hampel FC, Ratner PH, Van Bavel J, et al. Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device. Ann Allergy Asthma Immunol. 2010;105(2):168-173. Meltzer EO, LaForce C, Ratner P, Price D, Ginsberg D, Carr W. MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial of efficacy and safety. Allergy Asthma Proc. 2012;33(4):324-332. Andrews CP, Mohar D, Agarwal P, Salhi Y, Tantry SK. Efficacy and safety of once-daily and twice-daily olopatadine/mometasone nasal spray treatment in seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American College of Allergy, Asthma, and Immunology; October 26-30, 2017; Boston, MA. Ratner P, Hampel F, Breazna A, Caracta C, Tantry SK. Efficacy and safety of olopatadine/mometasone combination nasal spray for the treatment of seasonal allergic rhinits. Poster presented at: 75th annual meeting of the American College of Allergy, Asthma, and Immunology; October 26-30, 2017; Boston, MA.
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Hampel F, Pedinoff A, Jacobs R, Breazna A, Caracta C, Tantry S. Efficacy and safety of olopatadine/mometasone combination nasal spray in patients with seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American Academy of Allergy, Asthma, and Immunology; March 2-5, 2018; Orlando, FL. Berman G, Amar NJ, LaForce CF, Breazna A, Caracta C, Tantry SK. Rapid onset of action on nasal symptoms and ocular symptom improvement with olopatadine/mometasone combination nasal spray in patients with seasonal allergic rhinitis. Poster presented at: 75th annual meeting of the American Academy of Allergy, Asthma, and Immunology; March 2-5, 2018; Orlando, FL. Patel P, D'Andrea C, Sacks HJ. Onset of action of azelastine nasal spray compared with mometasone nasal spray and placebo in subjects with seasonal allergic rhinitis evaluated in an environmental exposure chamber. Am J Rhinol. 2007;21(4):499-503. Meltzer EO, Rickard KA, Westlund RE, Cook CK. Onset of therapeutic effect of fluticasone propionate aqueous nasal spray. Ann Allergy Asthma Immunol. 2001;86(3):286-291. Couroux P, Kunjibettu S, Hall N, Wingertzahn MA. Onset of action of ciclesonide once daily in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2009;102(1):62-68. Nasonex® (mometasone furoate monohydrate nasal spray). US prescribing information. Schering-Plough Corporation, Kenilworth, NJ; 2013. Bousquet J, Meltzer EO, Couroux P, et al. Onset of Action of the Fixed Combination Intranasal Azelastine-Fluticasone Propionate in an Allergen Exposure Chamber. J Allergy Clin Immunol Pract. 2018. Patel P, Salapatek AM, Talluri RS, Tantry SK. Pharmacokinetics of intranasal mometasone in the fixed-dose combination GSP301 versus two monotherapy intranasal mometasone formulations. Allergy Asthma Proc. 2018;39(3):232-239. Patel P, Salapatek AM, Talluri RS, Tantry SK. Pharmacokinetics of intranasal olopatadine in the fixed-dose combination GSP301 versus two monotherapy intranasal olopatadine formulations. Allergy Asthma Proc. 2018;39(3):224-231. Head K, Snidvongs K, Glew S, et al. Saline irrigation for allergic rhinitis. Cochrane Database Syst Rev. 2018(6).
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Figure 1. Study Design
During at-home dosing for 12 days, participants self-administered study drug approximately 12
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hours apart, based on treatment, without symptom assessment.
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Visit 2 EEC occurred approximately 24 hours before the first dose of study treatment; Visit 3 EEC was 10 hours, with 6 hours spent in the EEC immediately before the first dose of study
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treatment taken at 12 PM followed by an additional 4 hours after the first dose; Visit 4 EEC
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occurred approximately 1 hour after the morning (12 PM) dose on Day 14; Visit 5 EEC occurred approximately 6 hours after the last dose of study treatment taken at 12 AM on Day 14. The
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duration of EEC Visits 2, 4, and 5 was approximately 6 hours each. EC, exclusion criteria; EEC, environmental exposure chamber; IC, inclusion criteria.
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Figure 2. iTNSS Mean (SE) Change from Baseline (Visit 3) to End of Treatment (Visit 5) for GSP301 BID and QD Versus Placebo (ITT Population)
665 μg/mometasone 50 μg.
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine
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BID, twice-daily dosing; iTNSS, instantaneous Total Nasal Symptom Score; ITT, intention-to-
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treat; QD, once-daily dosing; SE, standard error.
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Figure 3. LS Mean (SE) of
Average iTNSS for GSP301 BID Versus Placebo (ITT Population) GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg.
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BID, twice-daily dosing; iTNSS, instantaneous Total Nasal Symptom Score; ITT, intention-to-
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treat; LS, least squares; SE, standard error.
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Olopatadine (n=36)
Placebo (n=36)
41.6 ± 11.4
42.1 ± 12.5
16 (44.4) 20 (55.6) 76.2 ± 17.2
16 (44.4) 20 (55.6) 76.0 ± 16.5
17 (47.2) 12 (33.3) 6 (16.7) 1 (2.8)
18 (50.0) 11 (30.6) 7 (19.4) 0 (0)
33 (91.7)
35 (97.2)
3 (8.3) 8.3 ± 2.1 4.2 ± 1.9
1 (2.8) 7.6 ± 2.2 4.3 ± 1.8
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Table 1. Demographics and Baseline Characteristics (Safety Population) GSP301 GSP301 BID AzeFlu QD (n=36) (n=36) (n=36) Age, mean ± SD, y 38.3 ± 10.8 44.9 ± 11.8 41.1 ± 10.0 Sex, n (%) Male 22 (61.1) 18 (50.0) 19 (52.8) Female 14 (38.9) 18 (50.0) 17 (47.2) Weight, mean ± SD, kg 82.0 ± 19.6 81.7 ± 14.2 83.3 ± 17.8 Race, n (%) White 20 (55.6) 14 (38.9) 20 (55.6) Black 9 (25.0) 13 (36.1) 13 (36.1) Asian 5 (13.9) 8 (22.2) 2 (5.6) Othera 2 (5.6) 1 (2.8) 1 (2.8) Ethnicity, n (%) Non-Hispanic or 32 (88.9) 31 (86.1) 30 (83.3) Latino Hispanic or Latino 4 (11.1) 5 (13.9) 6 (16.7) iTNSS, mean ± SDb 8.1 ± 2.3 8.2 ± 2.1 8.7 ± 2.5 iTOSS, mean ± SDb 4.3 ± 1.9 4.5 ± 2.3 4.8 ± 2.1
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. a Includes participants of mixed race and those that did not identify with the other mentioned race categories. b ITT population. BID, twice-daily dosing; FDA, Food and Drug Administration; iTNSS, instantaneous Total Nasal Symptom Score; iTOSS, instantaneous Total Ocular Symptom Score; ITT, intention-to-treat; QD, once-daily dosing; SD, standard deviation.
ACCEPTED MANUSCRIPT 23 Table 2. LS Mean Difference in Average iTNSS for Active Treatments Versus Placebo (ITT Population) Treatment Groups (T1 vs T2) n1, n2 LSMD 95% CI GSP301 BID versus Placebo 36, 35 -3.60 (-4.89, -2.30) GSP301 QD versus Placebo 36, 35 -3.05 (-4.35, -1.76) AzeFlu versus Placebo 34, 35 -2.83 (-4.05, -1.61) Olopatadine versus Placebo 36, 35 -0.81 (-2.00, 0.38)
P value <0.0001 <0.0001 <0.0001 0.179
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. BID, twice-daily dosing; CI, confidence interval; FDA, Food and Drug Administration; FDC, fixed-dose combination; iTNSS, instantaneous Total Nasal Symptom Score; ITT, intention-to-treat; LS, least squares; LSMD, least squares mean difference; QD, once-daily dosing; SE, standard error.
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AzeFlu (n=36)
Olopatadine (n=36)
Placebo (n=36)
9 (25.0)
8 (22.2)
6 (16.7)
3 (8.3) 1 (2.8) 2 (5.6) 0 (0) 5 (13.9) 0 (0) 0 (0)
4 (11.1) 1 (2.8) 2 (5.6) 2 (5.6) 6 (16.7) 0 (0) 0 (0)
3 (8.3) 0 (0) 0 (0) 0 (0) 3 (8.3) 0 (0) 0 (0)
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Table 3. Summary of Adverse Events (Safety Population) GSP301 GSP301 BID QD n (%) (n=36) (n=36) Participants reporting ≥1 8 (22.2) 11 (30.6) TEAE TEAEsa Headache 4 (11.1) 6 (16.7) Dysgeusia 2 (5.6) 1 (2.8) Epistaxis 0 (0) 0 (0) Rash 0 (0) 0 (0) Treatment-related TEAEs 7 (19.4) 5 (13.9) TEAEs leading to withdrawal 0 (0) 0 (0) SAEs 0 (0) 0 (0)
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GSP301 BID, sponsor olopatadine 665 μg/mometasone 25 μg; GSP301 QD, sponsor olopatadine 665 μg/mometasone 50 μg; AzeFlu, FDA-approved azelastine 137 μg/fluticasone 50 μg BID; Olopatadine, FDA-approved formulation 665 μg BID. a Occurring in ≥2% of participants in any treatment group. BID, twice-daily; FDA, Food and Drug Administration; QD, once-daily; SAE, serious adverse event; TEAE, treatmentemergent adverse event.