Ann Allergy Asthma Immunol 129 (2022) 618−626

Contents lists available at ScienceDirect

Efficacy and safety of GSP301 nasal spray in children aged 6 to

11 years with seasonal allergic rhinitis

Bruce M. Prenner, MD*; Niran J. Amar, MDy; Frank C. Hampel, Jr, MDz; Cynthia F. Caracta, MDx;
Wen Wu, PhDk
* Allergy Associates Medical Group, Inc, San Diego, California
y
Allergy Asthma Research Institute, Waco, Texas
z
Central Texas Health Research, New Braunfels, Texas
x
Glenmark Pharmaceuticals Inc, Paramus, New Jersey
k
Glenmark Pharmaceuticals Europe Ltd, Watford, United Kingdom

A R T I C L E I N F O A B S T R A C T

Article history:
Received for publication May 16, 2022.
Received in revised form July 6, 2022.
Accepted for publication July 24, 2022.
Background: GSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride
and the corticosteroid mometasone furoate.
Objective: To evaluate the efficacy, safety, and tolerability of GSP301 in pediatric patients (aged ≥6 to <12 years)
with seasonal allergic rhinitis (SAR).
Methods: This double-blind, randomized, parallel-group study randomized 446 eligible patients 1:1 (GSP301 [olopa-
tadine hydrochloride 665 mg and mometasone furoate 25 mg] or placebo) as 1 spray/each nostril twice daily for
14 days. The primary end point was change from baseline in average morning and evening subject-reported 12-hour
reflective Total Nasal Symptom Score (rTNSS) over a 14-day treatment period analyzed using mixed-effect model
repeated measures. Additional assessments included instantaneous Total Nasal Symptom Score, Pediatric Rhinocon-
junctivitis Quality of Life Questionnaire, reflective Total Ocular Symptoms Score, instantaneous Total Ocular Symp-
toms Score, individual symptoms, Physician-assessed Nasal Symptom Score, and adverse events.
Results: GSP301 showed clinically meaningful and statistically significant improvement in rTNSS vs placebo (0.6;
95% confidence interval, 0.9 to 0.2; P = .001). Statistically significant improvements favoring GSP301 were shown
for all individual rTNSS symptoms, instantaneous Total Nasal Symptom Score, and most of its individual symptoms,
Physician-assessed Nasal Symptom Score (P = .01), and Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (P
< .001). For ocular symptoms, numerical improvements favoring GSP301 were observed, with statistical significance
achieved only for reflective “tearing/watering eyes” (P = .04). Treatment-emergent adverse events occurred in 12.0%
and 10.4% of patients in the GSP301 and placebo groups, respectively. One subject (0.5%) (placebo group) experienced
a serious adverse event (suspected viral meningitis) that was not related to the study treatment and was resolved.
Conclusion: GSP301 was well tolerated and efficacious for treating SAR symptoms in pediatric patients and
showed a favorable safety profile.
Trial Registration: ClinicalTrials.gov Identifier: NCT03463031.
© 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access arti-
cle under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction chemokines, in addition to immunoglobulin E-mediated release of

Allergic rhinitis (AR) is a chronic inflammatory disease triggered
by exposure to allergens. The pathophysiology of AR is complex
and involves interaction between immune cells, cytokines, and
Reprints: Bruce M. Prenner, MD, Allergy Associates Medical Group, Inc, 5555 Reservoir
Drive, Suite 210, San Diego, CA 92120. E-mail: prenner@aaamg.com.
Disclosures: Dr Prenner received speaking fees from Optinose US, Inc and Merck Sharp
& Dohme, Inc and received research grants from Aldeyra Therapeutics, BELLUS Health,
Merck, Shionogi Inc, Teva Pharmaceuticals, and Genentech. Dr Hampel Jr and Dr Amar
were the site principal investigators on this study funded by Glenmark Specialty SA. Dr
Caracta is a former employee of Glenmark Pharmaceuticals Inc. Dr Wu is an employee
of Glenmark Pharmaceuticals Europe Ltd.
Funding: The study was funded by Glenmark Specialty SA.
bioactive mediators (such as histamine and leukotrienes), resulting
in AR symptoms.1-3 Typical AR symptoms include nasal congestion,
rhinorrhea, sneezing, and itching. Some patients also suffer from
nonnasal symptoms such as palate and inner ear itching, ocular
symptoms (itching/burning, watering, red, swollen eyes), cough,
fatigue, and irritability.4 Allergic rhinitis is traditionally categorized
according to its temporal pattern as seasonal AR (SAR) or perennial
AR (PAR). However, in some geographic areas, patients with SAR sen-
sitized to multiple allergens may have symptoms all year round, and
patients with PAR may have seasonal symptom exacerbations.3,5,6
Allergic rhinitis affects people of all ages from all countries and
ethnic groups and poses a significant medical and economic

https://doi.org/10.1016/j.anai.2022.07.029
1081-1206/© 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626
burden.3,4,6 In the United States, the prevalence of physician-diag-
nosed AR is nearly 1 in 7 adults and children.7,8 Allergic rhinitis has
an adverse impact on quality of life and physical and social function-
ing.3,6-9 In children and adolescents, AR can affect educational perfor-
mance and cognitive function,10-13 and AR history is associated with
the occurrence of asthma.14
There are 3 main approaches to AR management, which involve
avoidance of allergens, pharmacologic therapy, and allergen-specific
immunotherapy.4,6,15,16 Allergen avoidance may play a role in treating
AR but is often challenging or impossible for the patient. Pharmacologic
therapy is used to control or eliminate AR symptoms and represents
the standard of care for AR management. Allergen-specific immuno-
therapy targets the underlying AR pathophysiology and is generally
indicated when pharmacotherapy/allergen avoidance fail.17,18 The most
important pharmacologic drug categories include antihistamines (H1
receptor antagonists), corticosteroids, leukotriene receptor antagonists,
decongestants, mast cell stabilizers, and anticholinergics,4,6,15,16 with
intranasal corticosteroids (INCS), newer-generation antihistamines, or
combinations thereof being considered first-line AR therapies.6,18-21
Despite multiple treatment options, survey studies have shown that a
substantial proportion of patients feel dissatisfied with AR symptom
control and use multiple prescriptions and/or over-the-counter medica-
tions, switching back and forth between different products.8,22,23 How-
ever, for combinations of drugs, studies are often lacking that prove
their safety and efficacy based on modern evidence standards, raising
concerns about potential risks and questionable superiority to mono-
therapies.23 Using fixed-dosed combination therapies for AR whose effi-
cacy and safety have been confirmed in randomized controlled trials
can not only provide clinical benefits by targeting different molecular
pathways but also improve treatment adherence24 and reduce treat-
ment costs.25
GSP301 is a fixed-dose combination (FDC) of olopatadine hydro-
chloride (antihistamine) and mometasone furoate (corticosteroid)
developed as a single nasal spray (NS) for the treatment of SAR symp-
toms.26-33 The safety, tolerability, and efficacy of this FDC have been
evaluated in patients aged 12 years and older.26-33 GSP301 showed a
favorable safety profile and was well tolerated in single-dose,26,27
short-term (14 days),28-32 and long-term (52 weeks)33 clinical stud-
ies. Treatment with GSP301 provided statistically significant and clin-
ically meaningful improvement of SAR symptoms vs placebo and
monotherapies in patients exposed to a wide range of different pol-
lens28-31 associated with AR, with a rapid onset of action of 15
minutes28,30,31 (also confirmed in pooled analyses34-36 and meta-
analysis37), and significantly improved patients’ quality of life vs pla-
cebo.29-31,38 To date, GSP301 has been approved for the treatment of
SAR symptoms in patients aged 12 years and older in the United
States and more than 25 other countries.
The objectives of this double-blind, randomized, placebo-con-
trolled study were to evaluate the efficacy, safety, and tolerability of
GSP301 in pediatric subjects (aged ≥ 6 to < 12 years) with SAR. The
studied treatment regimen was 1 spray/each nostril twice daily for
14 days (each spray delivers 665 mg of olopatadine hydrochloride
and 25 mg of mometasone furoate). The daily dose corresponded to
half of the adult/adolescent GSP301 dosage (2 sprays/each nostril
twice daily) studied in phase 3 trials30−33 and matched pediatric daily
doses for marketed monotherapy NS products approved in the
United States.39,40
Methods
This study was conducted at 32 study sites in the United States in
2018. The protocol and its amendments were reviewed and approved
by the Chesapeake/Advarra Institutional Review Board (Columbia,
Maryland). All patients provided written informed consent, and
parents/legal guardians provided written informed consent.
619
Study Design
This was a phase 3, double-blind, randomized, parallel-group, pla-
cebo-controlled study in pediatric patients with SAR during the
spring or fall allergy season. The study included the following visits
or periods: single-blind placebo run-in period (7-10 days from the
Screening Visit to the Randomization Visit) and the 14-day double-
blind treatment period (Fig 1) with the Final/Discontinuation Visit on
day 15 (+ 2). After completion of the placebo run-in period, patients
who met the randomization criteria (eAppendix) were randomized
(1:1) to receive GSP301 (665 mg olopatadine hydrochloride and
25 mg mometasone furoate) or placebo (GSP301 vehicle). All treat-
ments were self-administered (with assistance from parents, guardi-
ans or caregivers, as needed) as 1 spray/each nostril twice daily.
Information on prohibited concomitant medications is provided in
the eAppendix.
Patients
Eligible patients were aged between 6 to 12 years with a clinical
history of SAR for at least 2 years before screening, with exacerba-
tions during the spring or fall allergy seasons for the relevant sea-
sonal allergen (eg, tree/grass pollen or ragweed pollen) and a positive
skin prick test result (wheal diameter ≥ 5 mm greater than the nega-
tive control) consistent with their medical history of SAR. Seasonal
allergic rhinitis must have been of sufficient severity to require treat-
ment in the past and throughout the study period. Patients were
required to have a 12-hour reflective Total Nasal Symptom Score
(rTNSS) of ≥ 6 for the morning (AM) assessment at the Screening
Visit. In addition, patients were expected to be adequately exposed
to the SAR allergen during the study period and were not allowed to
travel outside the known pollen area during the specified periods
(eAppendix).
The key exclusion criteria were any evidence or known history of
nasal polyps, other clinically significant respiratory tract malforma-
tions, nasal structural abnormalities or trauma or other conditions
that significantly interfere with the nasal air flow; acute or significant
chronic sinusitis or chronic purulent postnasal drip; active pulmo-
nary disorder or upper respiratory tract or sinus infection within the
14 days before screening or the development of respiratory infections
during the placebo run-in period; significant atopic dermatitis or rhi-
nitis medicamentosa (within 60 days before screening); and subcap-
sular cataracts, glaucoma, or other ocular disturbances. Additional
key exclusion criteria are provided in the eAppendix. Patients who
were known to be sexually active (and/or pregnant for girls) were
excluded and referred appropriately.
At each site, patients were screened only after the moderate pol-
len count criteria for the relevant pollen season were met (eAppen-
dix).
Assessments
Efficacy was assessed based on the patient-reported AR symptom
severity scores. With assistance from their parents, guardians or care-
givers (as needed), patients assessed their symptoms in the AM and
in the evening (PM) during the run-in and treatment periods before
administering the study drug, rated them on a 4-point severity scale
(from 0 = absent to 3 = severe) (eTable 1), and recorded the scores in
a diary. Reflective symptoms were assessed over the previous
12 hours, and instantaneous symptoms were assessed over the 10
minutes before dosing. The rTNSS and instantaneous TNSS (iTNSS)
were defined as the sum of 4 reflective/instantaneous nasal symptom
scores: nasal congestion, rhinorrhea, nasal itching, and sneezing
(maximum score of 12). The reflective and instantaneous Total Ocular
Symptom Scores (rTOSS and iTOSS, respectively) were defined as the
sum of 3 reflective/instantaneous ocular symptom scores: itching/
620 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626

Figure 1. Study design and patient disposition. The GSP301 group received 665 mg of olopatadine hydrochloride and 25 mg of mometasone furoate twice daily (1 spray/each nos-
tril). The Screening Visit (visit 1) was performed between day 10 and day 7 before the Randomization Visit (visit 2; day 1). The Treatment Visit (visit 3) was performed on day 8
(§ 2), and the Final or Discontinuation Visit (visit 4) was performed on day 15 (+ 2). No scheduled posttreatment follow-up visit was planned for this study. The superscript letter a
denotes one patient randomized to placebo received GSP301, and 1 patient randomized to GSP301 received placebo. For safety analyses, these patients were analyzed on the basis
of the actual treatment received. Efficacy analyses were based on the randomized treatment. The superscript letter b denotes 3 patients in the GSP301 group and 2 patients in the
placebo group were excluded from the full analysis set owing to lack of postbaseline primary efficacy end point assessment.

burning eyes, tearing/watering eyes, and redness of eyes (maximum
score of 9).
Additional efficacy assessments included the Physician-assessed
Nasal Symptom Score (PNSS)41 and the Pediatric Rhinoconjunctivitis
Quality of Life Questionnaire (PRQLQ).42 These assessments were per-
formed at the Randomization Visit and the Final or Discontinuation
Visit. Further details are provided in the eAppendix. Safety was
assessed based on adverse events (AEs) and serious AEs (SAEs);
measurements of vital signs (blood pressure and pulse rate), weight,
and height; eye examinations; focused ear, nose, and throat (ENT)
examinations; and physical examinations.
End Points
The primary end point was change from baseline in average AM
and PM patient-reported 12-hour rTNSS over the 14-day treatment
period. Secondary end points were (1) change from baseline in aver-
age AM and PM iTNSS over the 14-day treatment period; (2) change
from baseline in the overall PRQLQ score on day 15 (visit 4); and (3)
change from baseline in average AM and PM 12-hour rTOSS over the
14-day treatment period. Additional end points included changes
from baseline in average AM and PM iTOSS and reflective or instanta-
neous individual nasal and ocular symptom scores over the 14-day
treatment period and on each treatment day; and changes from base-
line in PNSS, physician-assessed individual nasal symptoms, and indi-
vidual PRQLQ domains on day 15 (visit 4). For rTNSS, iTNSS, rTOSS,
iTOSS, and their individual symptoms, baseline scores were derived
as the average of the previous 8 consecutive AM and PM assessments
during the placebo run-in period, including the AM assessment on
the day of randomization. For PRQLQ, PNSS, and their individual
symptoms or domains, baseline was defined as the score at the Ran-
domization Visit (before dosing).
Statistical Analysis
Efficacy was analyzed using the full analysis set (FAS), defined as
all randomized patients who received at least 1 dose of the study
drug (GSP301 or placebo) and had at least 1 postbaseline primary
efficacy assessment. Safety was analyzed using the safety analysis set
(SAS), defined as all randomized patients who received at least 1
dose of the study drug. Efficacy end points related to rTNSS, iTNSS,
rTOSS, and iTOSS were analyzed using the mixed-effect model
repeated measures, and end points related to PRQLQ and PNSS were
analyzed using the analysis of covariance model with change from
baseline as the dependent variable, treatment group and site as the
fixed effects, baseline score as the covariate, and study day as the
within-patient effect. More details are provided in the eAppendix. All
analyses were two-sided, and the statistical significance threshold
was set at P < .05. For all TNSS-related variables, differences with an
absolute value of > 0.23 units (direct anchor-based regression meth-
ods) were considered clinically meaningful (defined as the minimal
clinically important difference).43 For the primary and secondary end
 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626 621

Table 1 Table 2
Patient Demographic Characteristics (SAS) and Baseline Assessment Scores (FAS) Comparisons of Changes From Baseline in Total Nasal and Ocular Symptom Score for
GSP301 vs Placebo (FAS)
Demographics GSP301 (N = 225) Placebo (N = 221)
Variable Number of patients Comparisona (GSP301 vs placebo)
Age, mean (SD), y 8.7 (1.6) 8.6 (1.7)
Age group, n (%) GSP301 Placebo LSMD (95% CI) P
6 to < 9 y 100 (44.4) 99 (44.8)
9 to < 12 y 125 (55.6) 122 (55.2) Average AM and PM rTNSS 222 219 0.6 (0.9 to 0.2) .001
Sex, n (%) (primary end point)
Female 99 (44.0) 109 (49.3) Average AM and PM iTNSS 222 219 0.6 (1.0 to 0.3) < .001
Male 126 (56.0) 112 (50.7) Average AM and PM rTOSS 222 219 0.2 (0.6 to 0.1) .23
Racea, n (%) Average AM and PM iTOSS 222 219 0.1 (0.4 to 0.2) .59
White 170 (75.6) 171 (77.4)
Abbreviations: AM, morning; CI, confidence interval; FAS, full analysis set; iTNSS,
African American 48 (21.3) 46 (20.8)
instantaneous Total Nasal Symptom Score; iTOSS, instantaneous Total Ocular Symptom
Asian 8 (3.6) 5 (2.3)
Score; LSMD, least squares mean difference; PM, evening; rTNSS, reflective Total Nasal
Other 1 (0.4) 1 (0.5)
Symptom Score; rTOSS, reflective Total Ocular Symptom Score.
Ethnicity, n (%) a
Mixed-effect repeated measures model with change from baseline (over the 14-day
Hispanic or Latino 67 (29.8) 85 (38.5)
treatment period) as the dependent variable, treatment group and site as the fixed
Not Hispanic or Latino 158 (70.2) 135 (61.1)
effects, baseline score as the covariate, and study day as the within-patient effect. For
Missing data 0 (0.0) 1 (0.5)
rTOSS and iTOSS, treatment-by-site interaction was also used as the fixed effect.
Baseline assessment scores, mean (SD) GSP301 (N = 222) Placebo (N = 219)

Average AM and PM rTNSSb 8.83 (1.41) 8.84 (1.66)

Average AM and PM iTNSSb 7.89 (1.93) 7.82 (2.04)
Average AM and PM rTOSSb 3.84 (2.45) 3.59 (2.52) Table 3
Average AM and PM iTOSSb 3.54 (2.40) 3.26 (2.46) Comparisons of Changes From Baseline in Individual Nasal Symptom Scores for
PNSSc 7.8 (2.3) 7.8 (2.2) GSP301 vs Placebo (FAS)
PRQLQ (overall score)c 2.51 (1.08) 2.42 (1.00)
Variable Number of patients Comparisona (GSP301 vs placebo)
Abbreviations: AM, morning; FAS, full analysis set; iTNSS, instantaneous Total Nasal GSP301 Placebo LSMD (95% CI) P
Symptom Score; iTOSS, instantaneous Total Ocular Symptom Score; PM, evening;
rTNSS, reflective Total Nasal Symptom Score; rTOSS, reflective Total Ocular Symptom Average AM and PM reflective
Score; SAS, safety analysis set. Nasal congestion 222 219 0.1 (0.2 to 0.0) .048
a
If multiple races reported, data were counted in each race category. Rhinorrhea 222 219 0.1 (0.2 to 0.0) .02
b
Baseline score was the average of the previous 8 consecutive AM and PM assessments Nasal itching 222 219 0.2 (0.3 to 0.1) .002
during the placebo run-in period, including the AM assessment on the day of Sneezing 222 219 0.2 (0.3 to 0.1) < .001
randomization. Average AM and PM instantaneous
c
Baseline was the score at the Randomization Visit (visit 2; predose). Nasal congestion 222 219 0.1 (0.2 to 0.1) .002
Rhinorrhea 222 219 0.1 (0.2 to 0.0) .003
Nasal itching 222 219 0.1 (0.2 to 0.1) .41
points, a gate-keeping strategy was used with the following hierar- Sneezing 222 219 0.2 (0.3 to 0.1) < .001
chical order of end points: the primary end point, and the secondary
Abbreviations: AM, morning; CI, confidence interval; FAS, full analysis set; LSMD, least
end points (1), (2), (3) as indicated above. squares mean difference; PM, evening.
Demographic/baseline variables and safety evaluations were sum- a
Mixed-effect repeated measures model with change from baseline (over the 14-day
marized by treatment group, using descriptive statistics. All statistical treatment period) as the dependent variable, treatment group and site as the fixed
analyses were conducted using SAS statistical software version 9.4 effects, baseline score as the covariate, and study day as the within-patient effect.

(SAS Institute Inc). Sample size estimation is described in the eAp-

pendix. and PM reflective nasal symptoms also were statistically significant
and favored GSP301 (P < .05) (Table 3). When analyzed by each day,
statistically significant improvements in average AM and PM rTNSS
Results for GSP301 vs placebo were shown from day 3 to day 14 (P < .05)
Patient Demographics and Baseline Characteristics (Fig 2A).

A total of 446 patients aged greater than or equal to 6 to less than

Instantaneous Symptom Scores
12 years were randomized. Of those, 431 (96.6%) completed the
Like rTNSS, GSP301 treatment provided statistically significant
study; 446 were included in the SAS; and 441 were included in the
and clinically meaningful improvement in average AM and PM iTNSS
FAS (Fig 1). Most patients were White (>75%) and not Hispanic or
over the 14-day treatment period vs placebo (P < .001) (Table 2), and
Latino (>60%). The mean age was 8.7 years in the GSP301 and
this result met the prespecified gate-keeping strategy. Statistically
8.6 years in the placebo group, respectively. Nearly 45% of patients in
significant improvements in favor of GSP301 also were observed for
both groups were aged between 6 to 9 years. Demographic character-
all individual average AM and PM instantaneous nasal symptoms
istics and baseline assessment scores were comparable between the
except “nasal itching” (Table 3) and for change from baseline in aver-
treatment groups (Table 1).
age AM and PM iTNSS on each treatment day (P < .05) (Fig 2B).

Patient-Reported Nasal Symptoms

Reflective Symptom Scores
Treatment with GSP301 showed statistically significant and clini-
cally meaningful improvement from baseline in average AM and PM
12-hour rTNSS over the 14-day treatment period vs placebo
(P = .001), confirming the superiority of GSP301 to placebo according
to the primary end point (Table 2). Differences in changes from base-
line over the 14-day treatment period for all individual average AM
Patient-Reported Ocular Symptoms
Numerical improvements favoring GSP301 over placebo (with
least squares mean difference of 0.2 to 0.1) were observed for
average AM and PM rTOSS and iTOSS (Table 2) over the 14-day treat-
ment period and for all individual ocular symptoms except instanta-
neous “redness of eyes” (eTable 2). However, statistical significance
was achieved only for reflective “tearing/watering eyes” (P = .04). The
analysis by each day showed statistically significant differences to
622 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626

Figure 2. Comparisons of changes from baseline in average AM and PM Total Nasal Symptom Score for GSP301 vs placebo for each day (FAS). The analysis was performed using the
mixed-effect repeated measures model with change from baseline as the dependent variable; treatment group, site, and treatment-by-day interaction as the fixed effects; baseline
score as the covariate; and study day as the within-patient effect. Asterisk indicates a statistically significant difference (P < .05) vs placebo. AM, morning; FAS, full analysis set;
iTNSS, instantaneous Total Nasal Symptom Score; LS, least squares; PM, evening; rTNSS, reflective Total Nasal Symptom Score.

placebo for change from baseline in average AM and PM rTOSS in Safety

favor of GSP301 on day 6, day 7, and days 9 to 14 (P < .05) (eFig 1A).
By-day differences in changes from baseline in average AM and PM
iTOSS were statistically insignificant (eFig 1B).
Physician-Assessed Nasal Symptoms
Treatment with GSP301 resulted in statistically significant
improvement on day 15 in PNSS (P = .01) and in the scores for all phy-
sician-assessed individual nasal symptoms vs placebo (P < .05)
(Table 4).
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire
Treatment with GSP301 statistically significantly improved the
overall PRQLQ score on day 15 vs placebo (P < .001) (Table 4). This
result met the prespecified gate-keeping strategy (Methods). Statisti-
cally significant improvements in favor of GSP301 also were seen for
the PRQLQ domains “activity limitations,” “practical problems,” “nose
symptoms,” and “other symptoms” (P < .05), with the largest effect
size and the highest level of statistical significance being shown for
the domain “nose symptoms” (least squares mean difference of 0.6;
P < .001) (Table 4).
During the randomized treatment period, a compliance rate
between 75% to 125% was achieved by approximately 97% of patients
in each treatment group (SAS).
The percentage of patients reporting 1 or more treatment-emer-
gent AE (TEAE) was generally similar between the treatment groups,
with a greater percentage in the GSP301 than in the placebo group
(12.0% vs 10.4%) (Table 5). Treatment-emergent AEs experienced by
≥1% of patients in any treatment group were dysgeusia, headache,
epistaxis, and ear, nose, and throat (ENT) examination result abnor-
mal. Dysgeusia was observed only in the GSP301 group. Most TEAEs
observed in both treatment groups were considered to be unrelated
to the study treatment. All TEAEs, except for 1 event in 1 patient in
the placebo group, were mild or moderate in intensity. The only
severe event (suspected viral meningitis) was the only SAE observed
in the study, and it was considered not related to the study treat-
ment. The patient who experienced this SAE recovered; the study
treatment was not interrupted or discontinued, and the patient com-
pleted the study. Overall, 5 patients (1 patient in the placebo group
and 4 patients in the GSP301 group) discontinued the study during
the randomized treatment period owing to TEAEs. Treatment-emer-
gent AEs leading to study discontinuation were asthma (2 events),
conjunctivitis, otitis media acute, sinusitis, and oropharyngeal pain in
 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626 623

Table 4
Comparisons of Changes From Baseline in Pediatric Rhinoconjunctivitis Quality of Life Questionnaire score and Physician-assessed Nasal Symptom Score for GSP301 vs Placebo
(FAS)

Variable Number of patients with data available Comparisona (GSP301 vs placebo)

GSP301 Placebo LSMD (95% CI) P

PRQLQ (overall score) 222 219 0.3 (0.5 to 0.1) < .001
PRQLQ domains
Activity limitations 222 219 0.2 (0.5 to 0.0) .04
Practical problems 222 219 0.3 (0.4 to 0.1) .006
Nose symptoms 222 219 0.6 (0.9 to 0.4) < .001
Eye symptoms 222 219 0.1 (0.3 to 0.1) .20
Other symptoms 222 219 0.2 (0.4 to 0.0) .03
PNSS (overall score) 218 219 0.9 (1.5 to 0.2) .01
PNSS individual symptoms
Nasal congestion 218 219 0.2 (0.5 to 0.0) .02
Rhinorrhea 221 219 0.3 (0.4 to 0.1) < .001
Nasal itching 221 219 0.3 (0.4 to 0.1) < .001
Sneezing 221 219 0.2 (0.4 to 0.1) < .001

Abbreviations: CI, confidence interval; FAS, full analysis set; PNSS, Physician-assessed Nasal Symptom Score; PRQLQ, Pediatric Quality of Life Questionnaire.
a
Analysis of covariance evaluated change from baseline as the dependent variable, treatment group and site as the fixed effect, and baseline score as the covariate. For “practical
problems,” “nose symptoms,” “other symptoms,” baseline score-by-treatment interaction was included in the model. For overall PNSS and “nasal congestion,” treatment-by-site
interaction was included in the model.

Table 5
Summary of Adverse Events (SAS)

Category GSP301 (N = 225) Placebo (N = 221)

Number (%) of patients

Any TEAE 27 (12.0) 23 (10.4)
TEAEs occurring in ≥ 1% of patients in any treatment group
Dysgeusia 3 (1.3) 0 (0.0)
Headache 3 (1.3) 1 (0.5)
Epistaxis 2 (0.9) 5 (2.3)
Ear, nose, and throat examination result abnormal 3 (1.3) 3 (1.4)
Any TEAE related to the study treatment 7 (3.1) 6 (2.7)
Dysgeusia 3 (1.3) 0 (0.0)
Epistaxis 1 (0.4) 3 (1.4)
Nasal discomfort 0 (0.0) 1 (0.5)
Oropharyngeal pain 1 (0.4) 0 (0.0)
Ear, nose, and throat examination result abnormal 3 (1.3) 2 (0.9)
Any severe TEAE 0 (0.0) 1 (0.5)
Any moderate TEAE 6 (2.7) 10 (4.5)
Any mild TEAE 21 (9.3) 16 (7.2)
Any SAE 0 (0.0) 1 (0.5)
Any treatment-emergent SAE 0 (0.0) 1 (0.5)
Any TEAE leading to discontinuation of participation in the study 4 (1.8) 1 (0.5)
Upper respiratory tract infection 0 (0.0) 1 (0.5)
Otitis media 0 (0.0) 1 (0.5)
Otitis media acute 1 (0.4) 0 (0.0)
Conjunctivitis 1 (0.4) 0 (0.0)
Sinusitis 1 (0.4) 0 (0.0)
Asthma 2 (0.9) 0 (0.0)
Oropharyngeal pain 1 (0.4) 0 (0.0)
Deaths 0 (0.0) 0 (0.0)

Number of TEAEs

All TEAEs 33 31
Severity
Mild 25 18
Moderate 8 12
Severe 0 1a
Relationship to the study treatment
Related 9 7
Not related 24 24
TEAEs leading to discontinuation of participation in the study 6 2
Treatment-emergent SAEs 0 1a
Treatment-emergent SAEs related to the study drug 0 0

Abbreviations: SAE, serious adverse event; SAS, safety analysis set; TEAE, treatment-emergent adverse event.
NOTE. Patients with multiple events in the same category were counted only once in that category. Patients with events in more than 1 category were counted once in each cate-
gory. Percentages were based on the total number of patients in the SAS within each treatment group.
a
Suspected viral meningitis, resolved.
624 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626
the GSP301 group, and otitis media and upper respiratory tract infec-
tion in the placebo group. All TEAEs leading to study discontinuation,
except for 1 event (mild oropharyngeal pain) in 1 patient in the
GSP301 group, were considered not related to the study treatment.
All TEAEs leading to study discontinuation were resolved or were
being resolved, according to the last available data at the moment of
the clinical study report preparation. No deaths occurred in the study.
No clinically significant findings were observed for vital signs, physi-
cal examinations, focused ENT examinations, and eye examinations,
except for bilateral wheezing coincident with a TEAE (asthma) that
led to study discontinuation for 1 patient in the GSP301 group.
Discussion
Seasonal allergic rhinitis is highly prevalent in children and often
remains underdiagnosed and undertreated. Poorly controlled SAR
symptoms negatively affect the physical and emotional health of chil-
dren, their social lives, cognitive function, concentration, learning
capacity, and school performance and may have a detrimental impact
on comorbidities.10,13,44−46 The development of effective and safe
pharmacotherapies by conducting high-quality clinical trials is of
particular importance in children with SAR and can be considered an
ethical duty given the number of clinical trials in the pediatric popu-
lation is limited.
In the present study, 14-day twice-daily treatment with GSP301
FDC NS provided sustained, better clinically relevant and statistically
significant improvements in SAR nasal symptoms than did placebo in
children aged 6 to 11 years. A greater change from baseline in favor
of GSP301 was shown for average AM and PM subject-reported 12-
hour rTNSS over the 14-day treatment period (primary end point) in
addition to average AM and PM iTNSS. Improvements vs placebo
were not only statistically significant but also were considered clini-
cally meaningful in that the absolute values of least squares mean dif-
ferences between the groups (0.6 for both rTNSS and iTNSS) exceeded
the minimal clinically important difference of 0.23 units.43 When
analyzed by each day, statistically significant improvements were
seen from day 3 to day 14 for rTNSS and from day 1 to day 14 for
iTNSS. The superiority of GSP301 to placebo was also shown for all
individual reflective nasal symptoms (nasal congestion, rhinorrhea,
nasal itching, sneezing) and for all instantaneous nasal symptoms
except nasal itching. In addition, GSP301 considerably improved all
physician-assessed individual nasal symptoms and overall PNSS after
the end of treatment compared with baseline. The results of this
pediatric study are consistent with those of clinical trials investigat-
ing the efficacy of GSP301 in adults and adolescents (≥ 12 years of
age) with SAR.28−31,34,37 Taken together, these results provide con-
vincing evidence that GSP301 is efficacious for treating SAR nasal
symptoms in patients aged 6 years or older.
Ocular symptoms can be bothersome in patients with SAR. In this
study, treatment with GSP301 resulted in numerical improvements
in scores for reflective and instantaneous ocular symptoms, although
statistical significance was not achieved for all end points. Although
in the adult and adolescent GSP301 studies, statistically significant
ocular symptom improvements vs placebo was also
observed,28,30,31,36,37 this study was not specifically powered to
detect differences in ocular symptom changes vs placebo, so the non-
significance could be explained by a limited statistical power.
Seasonal allergic rhinitis has a profound effect on the quality of
life of children, causing sleep and mood impairment, daytime fatigue
and sleepiness, irritability, anxiety, embarrassment, practical prob-
lems, and activity limitation,44−47 resulting in psychosocial difficul-
ties and lost school days.13,46,47 In this study, GSP301 treatment
significantly improved patients’ quality of life. GSP301 was superior
to placebo in improving overall PRQLQ score in addition to scores for
PRQLQ domains “activity limitations,” “practical problems,” “nose
symptoms,” and “other symptoms” (all domains except “eye symp-
toms,” for which only numerical improvement was seen). This is in
line with the effect of GSP301 on SAR symptoms, particularly nasal
congestion, previously described as the most bothersome SAR symp-
tom in children and recognized as an important cause of sleep
disorders.44,48
In clinical practice, SAR symptom control is inadequate for many
patients.8,22,23 A promising strategy for better symptom relief is com-
bining SAR therapies targeting different disease pathways in a single
FDC. Moreover, using FDCs instead of separate drugs can positively
influence treatment compliance.24 The combination of nasally
applied corticosteroids and H1 receptor antagonists, which are the
mainstays of SAR treatment, allows exploitation of the properties of
both classes of these agents.49 Antihistamines inhibit the release of
histamine and other proinflammatory mediators and provide imme-
diate but short-term symptom relief, whereas INCS exhibit potent
anti-inflammatory, antipruritic, and vasoconstrictive effects and pro-
vide sustained symptom relief, but have a longer onset of action.49−51
When combined in a single device, these medications can provide a
rapid onset of action,28,30,31,36 sustained effect, and more complete
control of SAR symptoms, mitigating both the acute and late phases
of the immune response.49 The intranasal formulation allows the
delivery of higher drug concentrations to the affected area and avoid-
ance of systemic adverse effects.49,50 This approach has been success-
fully realized in the FDA-approved FDC NS containing the
antihistamine azelastine hydrochloride and the corticosteroid flutica-
sone propionate (AzeFlu), which has been proven to be effective and
safe in adult and pediatric patients aged 6 years and older,49,52−55 in
addition to being superior to fluticasone propionate in children53 and
to both components in adults.55 GSP301 contains other monocompo-
nents, olopatadine hydrochloride and mometasone furoate. Both
agents have long been used as intranasal SAR treatments in children
aged 6 to 11 years, with evidence of efficacy, safety, tolerability, and
negligible systemic exposure coming from randomized placebo- or
active-controlled clinical studies.56−58 The efficacy of GSP301 for
treating SAR shown in the present study, along with the data for Aze-
Flu, supports the overall benefit of the combination approach. The
effect size of AzeFlu on rTNSS changes vs placebo in children aged 6
to 11 years was comparable with that observed in the present study
(0.8 vs 0.6).52 The effects on the quality of life, as measured by the
difference in changes from baseline in the overall PRQLQ score on
day 15 vs placebo, were similar for AzeFlu and GS301 (0.3 for
both).52 =owever, it is important to note that direct cross-study com-
parisons are not possible because of differences in study design, pop-
ulation, and analysis.
GSP301 was found to be safe and well tolerated. In this study,
TEAEs occurred in similar proportions in both treatment groups
(12.0% in GSP301 and 10.4% in placebo), and most TEAEs were not
related to the study treatment. Only 1 SAE was observed in the study,
which occurred in the placebo group, was considered unrelated to
the study treatment, and did not lead to treatment/study discontinu-
ation. Except for this 1 SAE, the other TEAEs were of mild or moderate
intensity. The most frequent TEAEs in the GSP301 group were dys-
geusia (1.3%), headache (1.3%), ENT examination result abnormal
(1.3%), and epistaxis (0.9%), and the most frequent TEAEs in the pla-
cebo group were epistaxis (2.3%), ENT examination result abnormal
(1.4%), and headache (0.5%). Treatment-emergent AEs related to the
study treatment included dysgeusia and oropharyngeal pain (only in
the GSP301 group), nasal discomfort (only in the placebo group), epi-
staxis, and ENT examination result abnormal. Oropharyngeal pain
(mild) was the only drug-related TEAE that led to study discontinua-
tion. There were no cases of sedation, drowsiness, or nasal septal per-
foration. The safety outcomes observed in the present study
generally correspond to those reported in previous GSP301 studies in
adults and adolescents26−33 and are consistent with common adverse
effects associated with the use of olopatadine hydrochloride,56
 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626
mometasone furoate,57,58 and other INCS and intranasal
antihistamines44,59 including AzeFlu.52,54 Pharmacokinetic studies of
GSP301 in healthy adults showed low systemic exposure.26,27 Not
less importantly, long-term treatment with mometasone furoate in
children showed no evidence of suppression of the hypothalamic-
pituitary-adrenal axis and revealed no influence on their growth.58,60
This study has strengths and limitations. The strengths include
double-blind, randomized, placebo-controlled design, assessment of
both nasal and ocular SAR symptoms and of patients’ quality of life,
and the involvement of a total of 446 pediatric patients, with nearly
half of them aged 6 to 8 years. The limitation of this study is that it
was not designed to evaluate the GSP301 onset of action and its effi-
cacy vs monocomponents in the pediatric population (although in
adults and adolescents, GSP301 superiority to monotherapies was
shown28−31,34,35). Furthermore, pediatric studies have inherent limi-
tations related to the limited ability of children to assess and report
their symptoms. In this study, SAR symptoms were assessed using
reflective/instantaneous symptom scores originally designed for use
in adults, and patients assessed their symptoms with assistance from
their parents/guardians/caregivers (as needed). Caregivers may
underestimate symptom severity,52 and their help could possibly
explain the smaller effect of GSP301 treatment in relation to average
AM and PM rTNSS and iTNSS in children than in patients aged
12 years or more (0.6 in this study vs 0.9 in the pooled analysis of
studies in adults and adolescents34). Nevertheless, the effects in
younger children and in older children who were more likely not to
need adult help were equal in this study (rTNSS: 0.6; 95% CI, 1.1
to 0.1; P = .02 in children aged 6-8 years and 0.6; 95% CI, 1.1 to
0.2; P = .008 in children aged 9-11 years; FAS). An alternative expla-
nation of the smaller treatment effect in children than in adolescents
and adults may be lower symptom scores at baseline.
In conclusion, this study showed that GSP301 was efficacious for
treating SAR symptoms in patients aged 6 to 11 years when adminis-
tered as 1 spray/each nostril twice daily for 14 days and displayed a
favorable safety and tolerability profile. In addition, GSP301 treat-
ment had a positive impact on the quality of life of children with SAR.
Supplementary Data
Supplementary data related to this article can be found at https://
doi.org/10.1016/j.anai.2022.07.029
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Supplementary Data
eAppendix
Prohibited Concomitant Medications
The following medications were prohibited throughout the study
(from the Screening Visit to the Final/Discontinuation Visit) and for a
specified number of days before the Screening Visit: vasoconstrictors,
major tranquilizers (3 days before); oral/ocular/intranasal short-acting
antihistamines (5 days before); over-the-counter cough and cold prep-
arations/sleep aids containing antihistamines, topical/oral/intranasal
decongestants, over-the-counter food supplement/diet to reduce leu-
kotrienes, leukotriene antagonists or arachidonate 5-lipoxygenase
inhibitors, inhaled/oral/intranasal anticholinergics (7 days before);
long-acting antihistamines (10 days before); nedocromil or lodoxamide
(intranasal, ocular, or oral), cromolyn, ocular mast cell stabilizers, sys-
temic antibiotics, monoamine oxidase inhibitors, tricyclic antidepres-
sants (14 days before); inhaled/intranasal/topical/ocular corticosteroids
(except study medication and medications for the treatment of small,
localized lesions), investigational nonbiological drugs other than study
medication, strong CYP3A4 inducers or inhibitors (30 days before);
immunotherapy injections and immunosuppressive/immunomodulat-
ing medications (except topical pimecrolimus cream or tacrolimus oint-
ment if initiated at least 30 days before screening and maintained on
stable dosage), systemic corticosteroids (60 days before); immunoglob-
ulin E (IgE) antagonist or any other anti-IgE therapy, investigational
biological drugs, anti-interleukin-5 therapy (120 days before); sublin-
gual immunotherapy (180 days before); intranasal therapies (including
saline), ophthalmic drops (except for lens moisturizing drops), radia-
tion therapy, initiation of immunotherapy, any drug (investigational or
marketed) being used in another clinical study, herbal medication/sup-
plements to treat AR, or any other alternative therapies for AR, AR or
asthma preventive medications except for inhaled short acting beta-
agonists for mild asthma (up to 8 puffs per day), St John’s Wort, guaife-
nesin containing products (from screening).
Pollen Counts
Pollen counts were obtained each weekday, and when possible,
each weekend day at each investigational site. Three consecutive
days of moderate pollen counts were accepted as the start to the
given allergy season of the pollen. The definition of “moderate” var-
ied depending on the allergen. The American Academy of Allergy
Asthma and Immunology guideline (http://www.aaaai.org/global/
nab-pollen-counts/reading-the-charts.aspx) or local guidelines were
used to define moderate ranges for each allergen.
Additional Key Exclusion Criteria
Patients were not allowed to travel outside the known pollen area
for the investigational site for 24 hours or longer during the last
7 days of the screening/run-in period AND for 2 or more consecutive
days or 3 or more days in total between the Randomization Visit and
the Final/Discontinuation Visit. Other key exclusion criteria included
any history/evidence of the following conditions: anaphylaxis and/or
other severe local reaction(s) to skin testing; impaired hepatic func-
tion; systemic infection; hematological, hepatic, renal, endocrine dis-
order (except for hypothyroidism); gastrointestinal disease;
malignancy (excluding basal cell carcinoma); current neuropsycho-
logical condition with or without drug therapy; cardiovascular dis-
ease; respiratory disease other than mild asthma; dependence on
nasal, oral, or ocular decongestants, nasal topical antihistamines, or
nasal steroids; hypothalamic-pituitary-adrenal axis impairment;
known failure to show symptom improvement with any approved
626.e1
monotherapy component of the GSP301; history of a positive test
result for human immunodeficiency virus, hepatitis B or C.
Key Randomization Criteria
Go be randomized to study treatment, patients were required to
have an average rTNSS of ≥ 6 and an average reflective nasal congestion
score of ≥ 2 during the last 4 days of the placebo run-in period (average
of the previous 8 consecutive morning [AM] and evening [PM] assess-
ments from the PM assessment on day -4 to the AM assessment on the
day of randomization). Patients needed to have adequate symptom
assessment diary compliance defined as no missing entries on ≥ 2
assessment sessions during the last 4 days of the placebo run-in period
(from the PM assessment on day -4 to the AM assessment on the day of
randomization) and adequate study medication compliance (study
medication intake for at least 80% of the placebo run-in period).
Patients should not have had a common cold, upper/lower respiratory
infections, otitis, or acute sinusitis within the 14 days before the Ran-
domization Visit and should not have taken any prohibited concomi-
tant medications during the placebo run-in period. In addition to this,
patients had to meet the study inclusion and exclusion criteria.
Additional Assessment Details
Subject-Reported Allergic Rhinitis Symptom Scores
The AM assessments were to be performed before bathing, con-
sumption of food or beverages, or strenuous activities. The PM assess-
ments were to be performed approximately 12 hours after the AM
assessments.
Physician-Assessed Nasal Symptom Score
The investigators assessed the severity of the following signs/
symptoms: nasal congestion, rhinorrhea, nasal itching, and sneezing
as described in eTable 1 based on questioning the patients (overall
feeling since last visit); the ear, nose, and throat examination results;
and other observations by the Investigator.
Pediatric Rhinoconjuntivitis Quality of Life Questionnaire
The PRQLQ is a validated interviewer-administered questionnaire
developed to measure the physical, emotional, and social impair-
ments experienced by children (aged ≥6 to <12 years) with rhino-
conjunctivitis. The PRQLQ consists of 23 questions grouped in 5
domains: “activity limitation,” “practical problems,” “nose symp-
toms,” “eye symptoms,” and “other symptoms.” Subjects recalled
how they were/felt during the previous week and responded to each
question on a 7-point scale from 0 (not bothered/none of the time) to
6 (extremely bothered/all the time). The overall PRQLQ score was the
mean of all 23 responses. The individual domain scores were the
means of the items in those domains.
Sample Size
To assess the superiority of GSP301 to placebo, a sample size of 382
patients, allocated 1:1, would provide a 90% power to detect a between-
group mean difference of 1.0 units (assuming an SD of 3.0 and a 2-sided
alpha of 5%) in the absolute change from baseline in average AM and PM
subject-reported 12-hour rTNSS over the 14-day treatment period.
Assuming a drop-out rate of 15%, a total sample size of 450 randomized
patients (225 patients per treatment group) was selected for this study.
Statistical Analysis
Additional information for the analysis of efficacy end points
related to rTNSS, iTNSS, rTOSS, and iTOSS: treatment-by-site and
baseline score-by-treatment interactions (and treatment-by-day
626.e2 B.M. Prenner et al. / Ann Allergy Asthma Immunol 129 (2022) 618−626

interaction for by-day analyses) were investigated separately using estimates for rTNSS, iTNSS, rTOSS, and iTOSS, if there was no conver-
independent models and were included in the final model if they gence for the MMRM model with the treatment-by-day term, an
were statistically significant at a = 5% level. To present the by-day analysis of covariance model was used.

eTable 1
Description of the Severity Rating System for Nasal and Ocular Symptoms

Score Grade Description

0 Absent No sign/symptom evident

1 Mild Sign/symptom clearly present but minimal awareness; easily tolerated
2 Moderate Definite awareness of sign/symptom that is bothersome but tolerable
3 Severe Sign/symptom is hard to tolerate; causes interference with activities of daily living and/or sleeping

Reproduced from: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Allergic rhinitis: developing drug prod-
ucts for treatment. Guidance for industry. 2018. Available at: https://www.fda.gov/downloads/drugs/guidances/ucm071293.pdf. Accessed April 12, 2022.

eTable 2
Comparisons of Changes From Baseline in Individual Ocular Symptom Scores for GSP301 vs Placebo (FAS)

Number of patients Comparisona (GSP301 vs placebo)

Variable GSP301 Placebo LSMD (95% CI) P value

Average AM and PM reflective

Itching/burning eyes 222 219 0.1 (0.2 to 0.0) .09
Tearing/watering eyes 222 219 0.1 (0.2 to 0.0) .04
Redness of eyes 222 219 0.1 (0.2 to 0.0) .09
Average AM and PM instantaneous
Itching/burning eyes 222 219 0.1 (0.2 to 0.0) .08
Tearing/watering eyes 222 219 0.1 (0.2 to 0.1) .38
Redness of eyes 222 219 0.0 (0.1 to 0.0) .43

Abbreviations: AM, morning; CI, confidence interval; FAS, full analysis set; LSMD, least squares mean difference; PM, evening.
a
The analysis was performed using the mixed-effect repeated measures model with change from baseline (over the 14-day treatment period) as the dependent variable, treatment
group and site as the fixed effects, baseline score as the covariate, and study day as the within-patient effect.

eFigure 1. Comparisons of changes from baseline in average AM and PM Total Ocular Symptom Score for GSP301 vs placebo for each day (FAS). For rTOSS, the analysis of covariance
(ANCOVA) was performed with change from baseline as the dependent variable; treatment group, site, study day, and treatment-by-day interaction as the fixed effects; and baseline
as the covariate. For iTOSS, the analysis was performed using the mixed-effect repeated measures model with change from baseline as the dependent variable; treatment group, site,
and treatment-by-site interaction and treatment-by-day interaction as the fixed effects; baseline score as the covariate; and study day as the within-patient effect. Asterisk indicates
a statistically significant difference (P < .05) vs placebo. AM, morning; FAS, full analysis set; iTOSS, instantaneous Total Ocular Symptom Score; LS, least squares; PM, evening; rTOSS,
reflective Total Ocular Symptom Score.