Reimbursement Review

Olopatadine Hydrochloride and Mometasone Furoate Nasal Spray (Ryaltris)

Sponsor: Bausch Health, Canada Inc.

Therapeutic area: Seasonal allergic rhinitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Sources: Sponsor’s summary of clinical evidence¹ and product monograph.²

Introduction

Allergic rhinitis (AR) is an immunoglobulin E (IgE)–mediated inflammation of the nasal mucosa triggered by exposure to allergens.^3,4 AR has been categorized as seasonal allergic rhinitis (SAR) or perennial allergic rhinitis (PAR). AR is estimated to affect approximately 500 million people globally, irrespective of age or ethnic group.⁵ Studies suggest that the prevalence of AR varies by country but generally affects more than 25% of children and 40% of adults around the world.⁶ In Canada, AR is highly prevalent, affecting up to 20% to 25% of the population.⁷ SAR accounts for approximately 76.7% of AR cases. Based on these data, estimates of the prevalence of SAR in Canada range from 12.9% to 19.2%,^8,9 affecting approximately 3.5 million people. Patients often describe 1 or more of the following symptoms of AR: nasal congestion (stuffiness), nasal itching, rhinorrhea, sneezing, and cough.^4,10 AR is often accompanied by allergic conjunctivitis and is collectively known as allergic rhinoconjunctivitis,¹¹ which also includes ocular symptoms, such as itchiness, redness, and irritation of the eye.¹¹ Approximately 80% of SAR symptoms develop before the age of 20 years and peak at age 20 to 40 years before progressively declining.¹²

According to the clinical experts consulted by the review team, the management of moderate to severe SAR involves a comprehensive approach, with the goals of alleviating symptoms, improving quality of life, and minimizing symptom exacerbations. The clinical experts consulted by the review team noted that the goals of treatment are generally consistent across age groups (i.e., adults, adolescents, and children aged 6 years and older), but the approach to treatment and consideration of medication choices may vary across these age groups. Intranasal corticosteroids can be used alone or combined with oral or intranasal antihistamines.^13-15 According to the clinical experts consulted by the review team, intranasal corticosteroids alone or in combination with intranasal antihistamines are considered a first-line treatment option for moderate to severe SAR and generally preferred over oral antihistamines alone. The clinical experts consulted by the review team noted that fluticasone propionate, mometasone furoate, budesonide, ciclesonide, beclomethasone dipropionate, and fluticasone furoate are widely used or prescribed to reduce nasal inflammation and associated symptoms. Oral antihistamines are also used to manage itching, sneezing, and ocular symptoms, and would be considered as adjunctive therapy. According to the clinical experts consulted by the review team, second-generation nonsedating antihistamines, such as cetirizine, loratadine, desloratadine, fexofenadine, bilastine, and rupatadine, are used for the treatment of SAR instead of first-generation antihistamines. The clinical experts consulted by the review team noted that leukotriene receptor antagonists can be considered for the treatment of AR, particularly in patients who have concomitant asthma or those whose condition does not respond adequately to other therapies. The clinical experts consulted for this review noted that other pharmaceutical therapies that can be used in patients with AR include ocular antihistamines, mast cell stabilizers, and allergen immunotherapy or desensitization. Nonpharmacological management includes educating patients regarding allergen avoidance measures and environmental control measures, as well as saline nasal irrigation to help alleviate nasal symptoms and reduce the need for pharmacological treatments, according to the clinical experts consulted by the review team.

Olopatadine hydrochloride and mometasone furoate nasal spray (NS) (Ryaltris) contains 2 active substances: olopatadine hydrochloride and mometasone furoate. Olopatadine hydrochloride acts by selectively inhibiting the histamine-1 receptor and stabilizing mast cells to attenuate the inflammatory and allergic response experienced by patients with SAR.¹⁶ Mometasone furoate possesses anti-inflammatory, vasoconstrictive, and antipruritic properties.¹⁷ Mometasone furoate crosses cellular membranes to repress inflammatory gene transcription either directly or by activating the transcription of anti-inflammatory factors. Used together, olopatadine may trigger fast relief from the symptoms of SAR, while mometasone furoate may act to suppress the underlying allergic inflammatory reaction.^18,19 (In this Clinical Review Report, olopatadine hydrochloride and mometasone furoate NS is referred to as olopatadine-mometasone, and mometasone furoate NS is referred to as mometasone NS.)

The objective of this Clinical Review Report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of olopatadine-mometasone for the symptomatic treatment of moderate to severe SAR and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to the review team’s call for input and from the clinical experts consulted by the review team for the purpose of this review.

Patient Input

This review received patient group submissions from Asthma Canada and Allergy Quebec. Asthma Canada is a national charity focusing on improving the quality of life and health of people with asthma and respiratory allergies. Allergy Quebec is the main reference centre in Quebec for patients with food allergies and brings together allergists, nutritionists, pharmacists, institutions, and companies in the food sector. Asthma Canada collected patient input using its 2024 Annual Asthma Survey from a total of 1,407 patients and caregivers. Asthma Canada also conducted 2 one-on-one interviews with patients with AR who were selected at random from the participants who completed the AR section of the survey and provided their contact information. Allergy Quebec did not collect any input data from patients.

Both patient groups noted that AR can cause uncomfortable symptoms, including runny and/or itchy nose, nasal congestion, swollen and/or itchy eyes, headaches, sinus pain and/or pressure, and tiredness that negatively impact patients’ daily activities and quality of life. In total, 82% of the respondents to the Asthma Canada survey indicated that the physical symptoms are the most difficult and/or frustrating aspect of living with AR. Patients stated that finding a solution and/or treatment to eliminate or significantly lessen the symptoms of AR would be important for them, in particular, the elimination of rhinorrhea and relief of other symptoms, and more effective medications that do not trigger asthma flare-ups. Based on the survey data from Asthma Canada, just 43% of the participants reported that their current treatments can, or most of the time can, control their allergic symptoms, while 57% reported that current treatments do not control their symptoms. Based on the interview results from Asthma Canada, patient concerns included the lack of efficacy or lack of sustained efficacy, the undesired side effects (e.g., drowsiness, stuffy or dry nose), and the cost and problems with accessing some antihistamines (e.g., due to lack of insurance coverage or availability at local pharmacies).

Clinician Input

Input From the Clinical Experts Consulted by the Review Team

According to the clinical experts consulted by the review team, the main goals of the management of moderate to severe SAR include alleviating symptoms, improving quality of life, and minimizing symptom exacerbations. According to the clinical experts consulted by the review team, there were several unmet needs. For instance, not all patients respond adequately to the currently available treatments, particularly intranasal corticosteroids and oral antihistamines. A patient’s condition can also become refractory to current treatment options over time (e.g., due to escalation of eosinophilic inflammation that does not respond to first-line treatment with antihistamines). The clinical experts also noted the need for treatment options that offer better tolerability and can improve adherence.

According to the clinical experts consulted by the review team, olopatadine-mometasone can be used as a first-line treatment option, based on individual patient needs and treatment responses, by providing a dual-action therapy that combines an intranasal corticosteroid with an antihistamine. The clinical experts consulted by the review team noted that in clinical practice, intranasal corticosteroids alone are usually given to patients first because they can be given once daily and may be sufficient to treat symptoms. Intranasal corticosteroids combined with antihistamines are usually reserved for when intranasal corticosteroids alone are insufficient because the combination therapy is generally more costly, requires twice-daily administration, and may not be tolerated due to taste. Of note, the clinical experts consulted by the review team also noted that it is not necessary to trial monotherapy with an antihistamine or nasal corticosteroid before using olopatadine-mometasone.

According to the clinical experts consulted by the review team, the patients most suitable or most likely to respond to olopatadine-mometasone include the following:

• patients who are experiencing moderate to severe symptoms of SAR, have had an inadequate response to monotherapy with intranasal corticosteroids or antihistamines, and require both anti-inflammatory (intranasal corticosteroids) and antihistaminic or mast cell–stabilizing effects to effectively manage their symptoms

• patients whose quality of life is significantly impacted by SAR symptoms, affecting daily activities, sleep, and overall well-being.

According to the clinical experts consulted by the review team, the patients most suitable for treatment with olopatadine-mometasone would be identified through a clinical evaluation and symptom assessment, and noted that the assessment of symptom severity would occur through a physical examination and by obtaining a patient history. Conversely, the patients least suitable for olopatadine-mometasone include those with mild symptoms of SAR that are well controlled with monotherapy (either intranasal corticosteroids or antihistamines alone). The clinical experts consulted by the review team noted that allergy testing, such as skin prick tests or specific IgE testing, can identify the allergens triggering symptoms but is not required specifically for the initiation of olopatadine-mometasone.

According to the clinical experts consulted by the review team, in clinical practice, determining treatment response involves assessing various outcomes that reflect improvements in symptom control and overall quality of life. The clinical experts consulted by the review team noted that the typical outcomes used to assess response include reductions in the frequency and severity of nasal and ocular symptoms, such as congestion, sneezing, itching, rhinorrhea, and eye redness or watering. The clinical experts consulted by the review team noted that the extent to which these symptoms interfere with daily activities, sleep patterns, and productivity is evaluated, and assessments are conducted regularly, especially at the beginning of treatment and during peak allergy seasons, to ensure efficacy and to adjust therapy as needed. According to the clinical experts consulted by the review team, the outcomes used in clinical practice are generally aligned with those in clinical trials and include measurement of symptom scores, medication usage, and quality of life assessments. According to the clinical experts consulted by the review team, a clinically meaningful response to treatment varies according to many factors, including the patient population, the severity of initial symptoms, and the patient’s expectations, and may even vary among physicians based on their clinical experience.

The clinical experts consulted by the review team noted several situations when the discontinuation of olopatadine-mometasone should be considered, including lack of effectiveness, intolerable or persistent adverse events (AEs), or patient preference or adherence.

According to the clinical experts consulted by the review team, olopatadine-mometasone is suitable for treatment in various clinical settings, including in community settings, outpatient clinics in hospitals, and specialty allergy clinics. The clinical experts consulted by the review team noted that primary care physicians can diagnose and initiate treatment for patients with SAR and monitor treatment response through regular follow-up visits and adjust therapy as needed. According to the clinical experts consulted by the review team, although specialists such as allergists and immunologists or otolaryngologists may offer additional expertise in managing severe or refractory cases of AR, their involvement is not always required for routine diagnosis and management with olopatadine-mometasone.

Clinician Group Input

No clinician group input was received by the review team for this review.

Drug Program Input

Input was obtained from the drug programs that participate in the Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for olopatadine-mometasone:

• relevant comparators

• consideration for initiation of therapy

• consideration for prescribing of therapy

• generalizability

• system and economic issues.

Clinical Evidence

Systematic Review

Description of Studies

Three sponsor-conducted pivotal studies, GSP301-301, GSP301-304, and GSP301-305, were included in the sponsor-submitted systematic literature review (SLR). Both the GSP301-301 (N = 1,176) and GSP301-304 (N = 1,180) trials were phase III, double-blind randomized controlled trials (RCTs) that enrolled adolescent and adult patients (aged 12 years and older) with SAR. The primary objective of the GSP301-301 and GSP301-304 trials was to compare the efficacy of olopatadine-mometasone with placebo and the individual constituent monotherapies (i.e., olopatadine hydrochloride NS and mometasone NS) at the same dose in the same vehicle, and to assess the efficacy of olopatadine hydrochloride NS and mometasone NS versus placebo over 14 days of study treatment. Of note, olopatadine hydrochloride NS is not relevant to this Reimbursement Review because it is currently unavailable in Canada; therefore, results for olopatadine hydrochloride NS are not presented in this Clinical Review Report. The GSP301-305 trial (N = 446) was a phase III, double-blind, RCT investigating children (aged ≥ 6 to < 12 years) with SAR. The primary objective of the GSP301-305 trial was to assess the efficacy of olopatadine-mometasone relative to placebo over 14 days of study treatment. The primary end point of all 3 pivotal trials was patient-reported 12-hour reflective Total Nasal Symptom Score (rTNSS). The secondary efficacy and safety outcomes reported in the 3 pivotal trials included patient-reported 12-hour instantaneous Total Nasal Symptom Score (iTNSS), patient-reported 12-hour reflective Total Ocular Symptom Score (rTOSS), and harms, i.e., treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), withdrawals, and deaths. The health-related quality of life (HRQoL) outcomes evaluated in the trials included the Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities (RQLQ[S]) in the GSP301-301 and GSP301-304 trials, and the Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) in the GSP301-305 trial.

In the GSP301-301 and GSP301-304 trials, the mean age of patients was 39.3 years (standard deviation [SD] = 15.3 years) and 39.6 years (SD = 14.81 years), respectively. Across trials, most patients were female (64.6% and 62.9%, respectively). In the GSP301-301 trial, the baseline rTNSS score was the same across the olopatadine-mometasone group, the mometasone NS group, and the placebo group (mean = 10.1; SD = 1.2). In the GSP301-304 trial, the baseline mean rTNSS score was 10.1 (SD = 1.2) for the olopatadine-mometasone group, 10.3 (SD = 1.3) for the mometasone NS group, and 10.3 (SD = 1.2) for the placebo group. In the GSP301-305 trial, the mean age of the study population was 8.7 years (SD = 1.7 years), and there were slightly more males (56.0%) in the olopatadine-mometasone group, while in the placebo group, the proportion of male and female patients was similar (50.7% versus 49.3%). In the GSP301-305 trial, the baseline mean rTNSS score was 8.83 (SD = 1.41) for the olopatadine-mometasone group and 8.84 (SD = 1.66) for the placebo group.

Efficacy Results

Twelve-Hour rTNSS Over the 14-Day Treatment Period

In the full analysis set (FAS) for the GSP301-301 trial, the within-group least squares (LS) mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (standard error [SE] = not reported [NR]) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −0.98 points (95% confidence interval [CI], −1.38 to −0.57) between the olopatadine-mometasone group and the placebo group and −0.39 points (95% CI, −0.79 to 0.01) between the olopatadine-mometasone group and the mometasone NS group, with both point estimates of the LS mean difference favouring the olopatadine-mometasone group.

In the FAS of the GSP301-304 trial, the within-group LS mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −1.09 points (95% CI, −1.49 to −0.69) between the olopatadine-mometasone group and the placebo group and −0.47 points (95% CI, −0.86 to −0.08) between the olopatadine-mometasone group and the mometasone NS group, with both point estimates of the LS mean difference in favour of the olopatadine-mometasone group.

In the FAS of the GSP301-305 trial, the within-group LS mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in both treatment groups: ████ ██████ (SE = 0.18) in the olopatadine-mometasone group and ███ ████ ██████ (SE = 0.17) in the placebo group. The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −0.6 points (95% CI, −0.9 to −0.2) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Twelve-Hour iTNSS Over the 14-Day Treatment Period

In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and ███ █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.93 points (95% CI, −1.28 to −0.58) between the olopatadine-mometasone group and the placebo group and −0.36 points (95% CI, −0.71 to −0.01) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

In the FAS of the GSP301-304 trial, the within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.94 points (95% CI, −1.32 to −0.56) between the olopatadine-mometasone group and the placebo group and −0.51 points (95% CI, −0.88 to −0.13) between the olopatadine-mometasone group and the mometasone NS group, with both point estimates of the LS mean difference favouring the olopatadine-mometasone group.

In the FAS of the GSP301-305 trial, the within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in both treatment groups: ████ ██████ (SE = 0.17) in the olopatadine-mometasone group and ████ ██████ (SE = 0.17) in the placebo group. The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.6 points (95% CI, −1.0 to −0.3) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Twelve-Hour rTOSS Over the 14-Day Treatment Period

In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and ███ █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.49 points (95% CI, −0.79 to −0.19) between the olopatadine-mometasone group and the placebo group and −0.19 points (95% CI, −0.49 to 0.11) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

In the FAS of the GSP301-304 trial, the within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.52 points (95% CI, −0.84 to −0.20) between the olopatadine-mometasone group and the placebo group and −0.35 points (−0.66 to −0.03) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

In the FAS of the GSP301-305 trial, the within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in both treatment groups: | ████ ██████ ███ █ █████ in the olopatadine-mometasone group and ████ ██████ ███ █ █████ in the placebo group. The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.2 points (95% CI, −0.6 to 0.1) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

RQLQ(S) Overall Score on Day 15

In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in the RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: █████ ██████ (SE = NR) in the olopatadine-mometasone group, █████ ██████ (SE = NR) in the mometasone NS group, and ███ █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the RQLQ(S) overall score at day 15 was −0.43 points (95% CI, −0.64 to −0.21) between the olopatadine-mometasone group and the placebo group and −0.20 points (95% CI, −0.41 to 0.02) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

In the FAS of the GSP301-304 trial, the within-group LS mean change from baseline in the RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: | █████ █████ (SE = NR) in the olopatadine-mometasone group, | █████ ██████ (SE = NR) in the mometasone NS group, and ███ █████ ██████ (SE = NR) in the placebo group. The between-group LS mean difference in the RQLQ(S) overall score at day 15 was −0.45 points (95% CI, −0.68 to −0.22) between the olopatadine-mometasone group and the placebo group and −0.09 points (95% CI, −0.32 to 0.14) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

PRQLQ Overall Score on Day 15

In the FAS of the GSP301-305 trial, the within-group LS mean change from baseline in the PRQLQ overall score at day 15 showed an improvement in both treatment groups: | ████ ██████ ███ █ █████ in the olopatadine-mometasone group and ████ ██████ ███ █ █████ in the placebo group. The between-group LS mean difference in the PRQLQ overall score at day 15 was −0.3 points (95% CI, −0.5 to −0.1) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Harms Results

Treatment-Emergent Adverse Events

In the safety analysis set of the GSP301-301 trial, the proportion of patients experiencing TEAEs was 12.9% (39 out of 302) in the olopatadine-mometasone group, which was higher than in the mometasone NS group (7.1%; 21 out of 294) or in the placebo group (9.4%; 27 out of 287). The proportion of patients who had dysgeusia was 3.3% (10 out of 302) in the olopatadine-mometasone group, 0.7% (2 out of 287) in the placebo group, and 0% in the mometasone NS group. Headache occurred in 2.8% (8 out of 287) of the patients in the placebo group, a higher proportion than in the olopatadine-mometasone group (0.7%; 2 out of 302) or in the mometasone NS group (0.7%; 2 out of 294). █████████ ███ ████████ ██ ████ ███████ of the patients in the olopatadine-mometasone group, in 0.7% (2 out of 294) of the patients in the mometasone NS group, and ██ ████ ███████ of the patients in the placebo group.

In the safety analysis set of the GSP301-304 trial, the proportion of patients experiencing TEAEs was 15.6% (46 out of 294) in the olopatadine-mometasone group, higher than in the mometasone NS group (9.6%; 28 out of 293) or in the placebo group (9.5%; 28 out of 294). Dysgeusia was reported in 3.7% (11 out of 294) of the patients in the olopatadine-mometasone group and in 0% of patients in the mometasone NS and placebo groups. ████████ ████████ ██ ████ ███████ of the patients in the mometasone NS group, in ████ ███████ of the patients in the placebo group, and in 0 patients in the olopatadine-mometasone group. The proportion of patients who had epistaxis was 0.7% (2 out of 294) in the olopatadine-mometasone group, 1.0% (3 out of 293) in the mometasone NS group, and 1.0% (3 out of 294) in the placebo group.

In the safety analysis set of the GSP301-305 trial, the proportion of patients experiencing TEAEs was 12.0% (27 out of 225) in the olopatadine-mometasone group and 10.4% (23 out of 221) in the placebo group. The most common TEAE in the olopatadine-mometasone group was epistaxis (2.3%; 5 out of 225), while 0.9% (2 out of 221) of the patients in the placebo group had epistaxis. Dysgeusia was reported in 1.3% (3 out of 225) of the patients in the olopatadine-mometasone group and in 0% of patients in the placebo group. Headache occurred in 1.3% (3 out of 225) of the patients in the olopatadine-mometasone group and 0.5% (1 out of 221) of the patients in the placebo group.

Treatment-Emergent Serious Adverse Events

In the safety analysis set of the GSP301-301 trial, only 1 patient had a TESAE (0.3%), which was 1 spontaneous abortion in the olopatadine-mometasone group.

In the safety analysis set of the GSP301-304 trial, no patients in the olopatadine-mometasone group had a TESAE. One patient in the mometasone NS group (0.3%) had 1 TESAE (i.e., peritonsillar abscess), and 1 patient in the placebo group (0.3%) had 3 TESAEs (including 1 instance each of osteomyelitis, syncope, and foot fracture).

In the safety analysis set of the GSP301-305 trial, there was only 1 TESAE (i.e., meningitis), which was reported in 1 patient (0.5%) in the placebo group.

Withdrawals Due to TEAEs

In the safety analysis set of the GSP301-301 trial, no patients withdrew due to TEAEs in the olopatadine-mometasone group, while 4 patients in the mometasone NS group and 1 patient in the placebo group withdrew. The specific reasons for withdrawal were NR.

In the safety analysis set of the GSP301-304 trial, no patients withdrew due to TEAEs in the olopatadine-mometasone group or in the mometasone NS group. One patient in the placebo group (0.3%) discontinued due to a foot fracture.

In the safety analysis set of the GSP301-305 trial, 4 patients in the olopatadine-mometasone group (1.8%) withdrew due to TEAEs (1 instance each of conjunctivitis, acute otitis media, and sinusitis, and 1 upper respiratory tract infection) and 1 patient in the placebo group (0.5%) due to otitis media.

Mortality

No deaths were reported in the GSP301-301, GSP301-304, or GSP301-305 trials.

Critical Appraisal

The risk of bias arising from the randomization process was determined to be low for all 3 pivotal trials — that is, the GSP301-301 and GSP301-304 studies in adolescents and adults (aged 12 years and older) and the GSP301-305 study in children (aged ≥ 6 to < 12 years). The randomization processes were based on a computer-generated randomization scheme. Both the review team and the clinical experts consulted by the review team determined that the baseline characteristics were generally balanced across treatment groups within each of the 3 pivotal trials. The risk of performance bias due to the knowledge of treatment assignment was considered to be low by the review team because all 3 pivotal trials adopted a double-blind design, which masked the trial participants and trial personnel. An adherence rate of between 75% and 125% (i.e., twice a day for 14 days = 100%; twice a day for 17 days = 125%) was achieved by more than 90% of patients in each treatment group. The risk of bias due to missing outcome data was determined to be low for all 3 pivotal trials. Based on patient disposition information, a small proportion of patients in each treatment group of the 3 pivotal trials discontinued from the study for various reasons (e.g., loss to follow-up, withdrawal by patients, nonadherence). In all 3 pivotal trials, the analyses in the per-protocol analysis set, which excluded patients who had not adhered to the study protocol (defined as a major protocol violation), and the sensitivity analyses for rTNSS, which assumed the data missing were missing not at random, showed results consistent with those from the FAS (results NR) according to study investigators. Definitions for patient-reported symptom scores, including rTNSS (primary efficacy end point), iTNSS, and rTOSS were consistent across the 3 pivotal trials and considered accurate by the clinical experts consulted by the review team. However, because reflective and instantaneous symptom scales were designed primarily for assessment in adults, young children might need the assistance of a proxy to assess and report the severity of their symptoms. In the GSP301-305 trial, children assessed their symptoms with the assistance of their parents, guardians, or caregivers as needed. The possibility of underestimating the treatment difference between olopatadine-mometasone and placebo due to the assistance of a proxy remains unclear for the GSP301-305 trial. A gatekeeping strategy was used for rTNSS, iTNSS, and rTOSS in the GSP301-301 and GSP301-304 trials to adjust for multiplicity; however, multiplicity was not adjusted for RQLQ(S) in these 2 trials. In the GSP301-305 trial, adjustment for multiplicity was not carried out for any outcome.

Overall, the clinical experts consulted by the review team noted that the results from the 3 sponsor-submitted pivotal trials were generalizable to the Canadian context despite some potential issues. First, the Health Canada–approved indication is for patients with moderate to severe SAR. None of the 3 pivotal trials explicitly used the term “moderate to severe” in the trial eligibility criteria; rather, disease severity in the GSP301-301 and GSP301-304 trials was defined as patients with an rTNSS of 8 or greater (out of a possible 12 points) and a congestion score of 2 or more at the a.m. assessment at the screening visit, and patients with an rTNSS of 6 or greater (out of a possible 12 points) and a congestion score of 2 or more at the a.m. assessment at the screening visit in the GSP301-305 trial. According to the clinical experts consulted by the review team, these symptom score thresholds correctly reflect “moderate to severe” disease and were appropriate in the clinical trial setting to define patients with moderate to severe SAR. However, the clinical experts consulted by the review team also noted that in the clinical setting, these symptom score thresholds are typically not required to determine a patient’s disease severity. Instead, a determination of disease severity relies on a clinician’s judgment based on the extent to which patients are impacted by their symptoms. Second, the clinical experts consulted by the review team noted that, from the perspective of real-world clinical practice, the exclusion criteria of the 3 pivotal trials were restrictive. For instance, according to the clinical experts, patients with nasal structural abnormalities and patients with a history of significant rhinitis medicamentosa were excluded from the 3 pivotal trials while, in clinical practice, these patients might still be eligible for and benefit from olopatadine-mometasone. Despite these potential concerns, the experts consulted by the review team noted that the trial eligibility criteria were still reflective of the patients they would see in the real world and may be generalized to a broader population. The clinical experts also noted that the 14-day treatment duration used in the pivotal trials might not be reflective of the duration of treatment in the real-world clinical setting, where patients are often given treatment for a longer period. Furthermore, the clinical experts highlighted that adherence to treatment in all 3 pivotal trials was higher than they would expect to see in the real world, which may overestimate the treatment effect that would be observed in a real-world setting.

GRADE Summary of Findings and Certainty of the Evidence

Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty-of-evidence assessment for the rTNSS, iTNSS, rTOSS, RQLQ(S), and PRQLQ were set according to the presence of an important effect based on thresholds agreed upon by the clinical experts consulted by the review team for this review. For harm events, the certainty of evidence was summarized narratively.

For the GRADE assessments, the findings from the GSP301-301 and GSP301-304 trials were considered together and summarized narratively per outcome and per comparison because these studies were similar in population, interventions, design, and outcome measures. The findings from the GSP301-305 trial were assessed individually because the GSP301-305 trial had a child population (aged ≥ 6 to < 12 years), while the GSP301-301 and GSP301-304 trials had an adolescent and adult population (aged 12 years and older).

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• Nasal symptoms: 12-hour rTNSS, 12-hour iTNSS

• Ocular symptoms: 12-hour rTOSS

• HRQoL outcomes: RQLQ(S), PRQLQ

• Harms: TESAEs.

Results of GRADE Assessments

Olopatadine-Mometasone Versus Placebo

Table 2 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for adolescent and adult patients (aged 12 years and older) with SAR.

Table 4 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for children (aged ≥ 6 to < 12 years) with SAR.

Olopatadine-Mometasone Versus Mometasone Monotherapy

Table 3 presents the GRADE summary of findings for olopatadine-mometasone versus mometasone NS for adolescent and adult patients (aged 12 years and older) with SAR.

Table 2: Summary of Findings for Olopatadine-Mometasone Versus Placebo for Adolescent and Adult Patients (Aged 12 Years and Older) With SAR

CI = confidence interval; HRQoL = health-related quality of life; iTNSS = instantaneous Total Nasal Symptom Score; LS = least squares; MID = minimal important difference; mometasone NS = mometasone furoate nasal spray; NR = not reported; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RCT = randomized controlled trial; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SAR = seasonal allergic rhinitis; TESAE = treatment-emergent serious adverse event.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aCertainty of evidence was not rated down because there were no serious concerns in risk of bias, indirectness, inconsistency, and imprecision.

^bRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour rTOSS in both the GSP301-301 and GSP301-304 trials crossed the MID, with point estimates favouring olopatadine-mometasone, despite that the point estimates were very close to the MID.

^cRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of LS mean change from baseline in the RQLQ(S) overall score in both the GSP301-301 and GSP301-304 trials crossed the MID, with point estimates favouring olopatadine-mometasone.

^dRated down 1 level for imprecision due to small number of events.

Sources: Clinical Study Reports for the GSP301-301²⁰ and GSP301-304²¹ trials and sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Table 3: Summary of Findings for Olopatadine-Mometasone Versus Mometasone NS for Adolescent and Adult Patients (Aged 12 Years and Older) With SAR

CI = confidence interval; HRQoL = health-related quality of life; iTNSS = instantaneous Total Nasal Symptom Score; LS = least squares; MID = minimal important difference; mometasone NS = mometasone furoate nasal spray; NR = not reported; NS = nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RCT = randomized controlled trial; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; TESAE = treatment-emergent serious adverse event.

Note: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour rTNSS in the GSP301-301 and GSP301-304 trials included the MID, with point estimates favouring olopatadine-mometasone.

^bRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour iTNSS in both the GSP301-301 and GSP301-304 trials included the MID, with point estimates favouring olopatadine-mometasone.

^cRated down 1 level for inconsistency: The point estimate of the LS mean change from baseline in average a.m. and p.m. 12-hour rTOSS was near the no-effect line (i.e., 0) for the GSP301-301 trial and near the MID (i.e., 0.5) specified by the clinical experts consulted by the review team for the GSP301-304 trial. A fair proportion of the 95% CI crossed the no-effect line for the GSP301-301 trial, while the 95% CI excluded the no-effect line for the GSP301-304 trial. Rated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour rTOSS in the GSP301-301 and GSP301-304 trials included the MID, with point estimates favouring olopatadine-mometasone.

^dCertainty of evidence was not rated down as there were no serious concerns in risk of bias, indirectness, inconsistency, and imprecision.

^eRated down 1 level for imprecision due to small number of events.

Sources: Clinical Study Reports for the GSP301-301²⁰ and GSP301-304²¹ trials and sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Table 4: Summary of Findings for Olopatadine-Mometasone Versus Placebo for Children (Aged From 6 Years to Younger Than 12 Years) With SAR

CI = confidence interval; HRQoL = health-related quality of life; iTNSS = instantaneous Total Nasal Symptom Score; LS = least squares; MID = minimal important difference; NR = not reported; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SAR = seasonal allergic rhinitis; TESAE = treatment-emergent serious adverse event.

Note: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour rTNSS in the GSP301-305 trial included the MID, with the point estimate favouring olopatadine-mometasone and excluding MID.

^bRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour iTNSS in the GSP301-305 trial included the MID, with the point estimate favouring olopatadine-mometasone and excluding MID.

^cRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in average a.m. and p.m. 12-hour rTOSS in the GSP301-305 trial included the MID, with the point estimate favouring olopatadine-mometasone.

^dRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of > 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of the LS mean change from baseline in the PRQLQ overall score in the GSP301-305 trial included the MID, with the point estimate favouring olopatadine-mometasone.

^eRated down 1 level for imprecision due to small number of events.

Sources: Clinical Study Report for the GSP301-305²³ trial and sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Long-Term Extension Studies

A long-term extension study that evaluated the long-term (52 weeks) safety, tolerability, and efficacy of olopatadine-mometasone in adults and adolescents (aged 12 years and older) with PAR was submitted by the sponsor. However, given that the Health Canada–approved indication is for the treatment of SAR, not PAR, the long-term study submitted by the sponsor was not considered relevant to this review and was therefore not appraised.

Indirect Comparisons

Description of Studies

The indirect treatment comparisons (ITCs) submitted by the sponsor included 2 network meta-analyses (NMAs). One NMA evaluated the efficacy of olopatadine-mometasone compared with placebo, intranasal corticosteroids, and oral antihistamines in adolescent and adult patients (aged 12 years and older) with SAR. The other NMA assessed the efficacy of olopatadine-mometasone relative to placebo and intranasal corticosteroids in children (aged ≥ 6 to < 12 years) with SAR. The NMA for adolescent and adult patients was based on 13 RCTs identified from a sponsor-conducted SLR, while the NMA for children was based on 4 RCTs. Efficacy was measured using 12-hour rTNSS in both NMAs.

Efficacy Results

The NMA in Adolescent and Adult Patients Aged 12 Years and Older

In the base-case analysis, the mean or LS mean difference in the 12-hour rTNSS was −1.26 points (95% credible interval [CrI], −1.86 to −0.67) between the olopatadine-mometasone and placebo arms, −0.27 points (95% CrI, −0.87 to 0.33) between the olopatadine-mometasone and intranasal corticosteroids arms, and −0.91 points (95% CrI, −1.91 to 0.06) between the olopatadine-mometasone and oral antihistamines arms. Results from the sensitivity analyses were generally consistent with the results in the base-case analysis.

The NMA in Adolescent and Child Patients Aged From 6 Years to Younger Than 12 Years

In the base-case analysis, the mean or LS mean difference in the 12-hour rTNSS was −1.21 points (95% CrI, −1.86 to −0.56) between the olopatadine-mometasone and placebo arms and −0.94 points (95% CrI, −1.63 to −0.26) between the olopatadine-mometasone and intranasal corticosteroids arms. No sensitivity analyses were conducted.

Harms Results

Harms data were not examined in either NMA submitted by the sponsor.

Critical Appraisal

The 2 NMAs submitted by the sponsor defined the review questions (i.e., population, intervention, comparator, outcomes, and study design) a priori. With respect to comparators in the SLR protocol, the sponsor listed several active comparators under 2 drug classes: intranasal corticosteroids and oral antihistamines. The clinical experts consulted by the review team noted that some relevant comparators that were approved by Health Canada for the treatment of the symptoms of SAR were missing from the 2 classes in the protocol, including fluticasone furoate, bilastine, and rupatadine fumarate. No rationale was provided for why these comparators were not included. Consequently, these missing relevant comparators from the SLR protocol might have resulted in missing evidence in the subsequent NMAs, although the impact of this potential bias remains unknown. In addition, there is a possibility that missing comparators may jeopardize the generalizability of the NMA results to these missing comparator therapies.

To form a network, the individual treatments identified from the included studies were categorized into corresponding nodes: olopatadine-mometasone, intranasal corticosteroids, oral antihistamines, and placebo. The sponsor assumed that individual drugs in the same drug class were equivalent in terms of clinical efficacy (intraclass clinical equivalency), which was considered reasonable by the clinical experts consulted for this review. However, it was noted that within some nodes, there were only 1 or 2 individual drugs included due to a lack of eligible studies, which was beyond the sponsor’s control. For instance, only loratadine was available and included in the oral antihistamine node in the adolescents and adults NMA. In the children NMA, the intranasal corticosteroid node consisted only of mometasone and ciclesonide. The review team determined that there was a concern and associated uncertainty regarding whether only 1 or 2 individual therapies would properly represent the corresponding drug class in terms of efficacy. Thus, the interpretation of the efficacy of olopatadine-mometasone relative to the intranasal corticosteroid class and to the oral antihistamine class should be made with caution.

The clinical experts consulted by the review team generally agreed with the sponsor’s evaluation and identified no serious heterogeneity arising from the patient and disease characteristics examined in the NMAs (i.e., age, sex, disease duration, baseline symptom scores, comorbidity). However, the clinical experts consulted by the review team also noted that some patient or disease characteristics that might be potential sources of heterogeneity were missing from the sponsor-conducted NMAs, including urban versus rural living conditions, genetic predisposition, family history of atopic diseases, and smoking or vaping status. Thus, some uncertainty concerning the results of the NMA is warranted due to these potential sources of heterogeneity; however, the inclusion of these variables was beyond the sponsor’s control, given the limited data available in the included studies.

Studies Addressing Gaps in the Evidence from the Systematic Review

No studies addressing gaps in the pivotal and RCT evidence were submitted by the sponsor.

Conclusions

The sponsor submitted 3 phase III, double-blind, RCTs: GSP301-301, GSP301-304, and GSP301-305. Both the GSP301-301 (N = 1,176) and GSP301-304 (N = 1,180) trials compared the efficacy of olopatadine-mometasone with placebo and the individual constituent monotherapies (i.e., olopatadine hydrochloride NS and mometasone NS) in adolescent and adult patients (aged 12 years and older) with SAR, while the GSP301-305 trial (N = 446) assessed the efficacy of olopatadine-mometasone relative to placebo in children (aged ≥ 6 to < 12 years) with SAR. Compared with placebo, the evidence from the 3 pivotal trials showed added clinical benefits of olopatadine-mometasone in reducing nasal and ocular symptoms. Results from the GSP301-301 and GSP301-304 trials suggested with moderate to high certainty that olopatadine-mometasone, compared with placebo, results in an improvement in the 12-hour rTNSS, 12-hour iTNSS, and 12-hour rTOSS in adolescent and adult patients with SAR. Evidence from the GSP301-305 trial also suggested improvements in rTNSS and iTNSS with olopatadine-mometasone compared with placebo with moderate certainty, but not for ocular symptoms. Compared with mometasone NS in adolescent and adult patients, although the results for nasal and ocular symptoms favoured olopatadine-mometasone, they were not clinically meaningful. Olopatadine-mometasone was considered safe in adults, adolescents, and children with SAR because the harms observed in patients treated with olopatadine-mometasone were expected and manageable, given the known safety profiles of the individual excipients.

The indirect evidence submitted by the sponsor included 1 NMA in adolescent and adult patients with SAR and 1 NMA in children with SAR. The results of the NMAs were consistent with the pivotal trial, favouring olopatadine-mometasone over placebo in both analysis populations. In the NMA in children, olopatadine-mometasone was favoured over intranasal corticosteroids, but there was no difference between these treatments in the adolescents and adults NMA. There was also no difference between olopatadine-mometasone and oral antihistamines in the adolescents and adults NMA. Overall, the findings from the 2 NMAs were uncertain due to limitations surrounding the comparators considered and whether there was appropriate representation in the comparator drug classes in terms of efficacy.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of olopatadine-mometasone (Ryaltris), 25 mcg mometasone NS, and placebo for the symptomatic treatment of moderate to severe SAR and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

AR is an IgE-mediated inflammation of the nasal mucosa triggered by exposure to allergens.^3,4 AR has been categorized as SAR or PAR. Generally, SAR is induced by pollen whereas PAR is induced by allergens, such as those from animals and dust mites.^3,4,11 It is estimated to affect approximately 500 million people globally, irrespective of age or ethnic group.⁵ Studies suggest that the prevalence of AR varies by country, but generally affects more than 25% of children and 40% of adults around the world.⁶ It is also widely acknowledged that the prevalence of SAR is increasing globally, as it has been shown to have risen significantly in the past 2 decades.^9,10,13 This trend has been attributed to several factors, such as global urbanization, changing global climate conditions, improvements in hygiene, changes in diet, and increased obesity.^9,10

Patients often describe 1 or more of the following classic symptoms of AR: nasal congestion (stuffiness), nasal itching, rhinorrhea, sneezing, and cough.^4,10 AR is often accompanied by allergic conjunctivitis and is collectively known as allergic rhinoconjunctivitis,¹¹ which also includes ocular symptoms, such as itchiness, redness, and irritation of the eye.¹¹ The incidence rate of AR in children over the first 5 years of life was reported to be 17.2%, with a peak age at diagnosis of between 24 and 29 months (2.5%).²⁴ Meta-analysis studies demonstrate that there are sex-specific differences in the prevalence of AR, namely a male predominance in childhood but a female predominance in adolescents.^25,26 Approximately 80% of SAR symptoms develop before the age of 20 years and peak at age 20 to 40 years before progressively declining.¹² AR impairs patients’ quality of life, social life, and attendance and productivity at school and work, and is associated with substantial economic costs.⁷

In Canada, AR is highly prevalent, adversely affecting up to 20% to 25% of the population.⁷ SAR accounts for approximately 76.7% of AR cases. Based on these data, estimates of the prevalence of SAR in Canada range from 12.9% to 19.2%.^8,9 Considering this, it is estimated that approximately 3.5 million people in Canada may be affected by moderate to severe SAR.²⁷ However, this number may be larger because it has been suggested that there is substantial underdiagnosis of AR in Canada.⁷

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

According to the clinical experts consulted for this review, the management of moderate to severe SAR involves a comprehensive approach, with the goals of alleviating symptoms, improving quality of life, and minimizing symptom exacerbations. The clinical experts consulted by the review team noted that the goals of treatment are generally consistent across age groups (i.e., adults, adolescents, and children aged 6 years and older), but the approach to treatment and consideration of medication choices may vary across these age groups. According to the clinical experts consulted by the review team, the choice of medications in children and adolescents should consider factors such as age-appropriate formulations (e.g., nasal sprays versus pills versus syrup), appropriate dosing, safety profiles, potential impact on growth and development, and caregiver involvement in adherence to treatment plans. For instance, the clinical experts consulted by the review team noted that monitoring for side effects, especially growth suppression with long-term intranasal corticosteroids use, is important in younger patients. Consideration of how AR affects sleep, school attendance, social activities, and overall well-being is also important.

Several options for pharmaceutical management are available for moderate to severe SAR, including intranasal corticosteroids, oral antihistamines, leukotriene receptor antagonists, and allergen immunotherapy or desensitization.¹⁵ Intranasal corticosteroids can be used alone or combined with oral or intranasal antihistamines.^13-15 According to the clinical experts consulted by the review team, intranasal corticosteroids alone or combined with intranasal antihistamines are considered as first-line treatment options for moderate to severe SAR and are generally preferred over oral antihistamines alone. The clinical experts consulted by the review team noted that fluticasone propionate, mometasone furoate, budesonide, ciclesonide, beclomethasone dipropionate, and fluticasone furoate are widely used or prescribed to reduce nasal inflammation and associated symptoms.

Oral antihistamines are also used to manage itching, sneezing, and ocular symptoms. According to the clinical experts consulted by the review team, oral antihistamines would be considered as adjunctive therapy due to being less effective than intranasal corticosteroids for nasal congestion. First-generation antihistamines (e.g., diphenhydramine and hydroxyzine) are no longer suggested due to various adverse side effects impacting the central nervous system, anticholinergic side effects, and cardiac toxicity.¹⁵ According to the clinical experts consulted by the review team, second-generation nonsedating antihistamines, such as cetirizine, loratadine, desloratadine, fexofenadine, bilastine, and rupatadine, are used for the treatment of SAR.

Leukotriene receptor antagonists, such as montelukast, are also approved in Canada for the treatment of AR.¹⁶ The clinical experts consulted by the review team noted that leukotriene receptor antagonists are generally considered for patients with AR who have concomitant asthma or those whose condition does not respond adequately to other therapies. However, the clinical experts consulted for this review noted that leukotriene receptor antagonists have become less preferred in clinical practice due to their side effect profile, including sleep and mood disturbances.

According to the clinical experts consulted by the review team, other pharmaceutical therapies that may be used in patients with AR include ocular antihistamines, mast cell stabilizers, and allergen immunotherapy or desensitization. The clinical experts consulted by the review team noted that ocular antihistamines and mast cell stabilizers are used for managing allergic conjunctivitis symptoms as an adjunct therapy, and olopatadine and ketotifen have been approved by Health Canada for allergic conjunctivitis and are commonly used in clinical practice. According to the clinical experts, allergen immunotherapy or desensitization may be used to treat patients with AR when specific criteria are met, such as when the aforementioned medications are not enough to alleviate symptoms, the patient wishes to decrease medication use, or the patient is intolerant of the aforementioned medications.

According to the clinical experts consulted by the review team, nonpharmacological management includes educating patients about allergen avoidance measures and environmental control measures, as well as the use of saline nasal irrigation to help alleviate nasal symptoms and reduce the need for pharmacological treatments.

Drug Under Review

Olopatadine-mometasone (Ryaltris) contains 2 active substances: olopatadine hydrochloride and mometasone furoate. Olopatadine acts by selectively inhibiting the histamine-1 receptor and stabilizing mast cells to attenuate the inflammatory and allergic response experienced by patients with SAR.¹⁶ As an anti-inflammatory drug, when applied intranasally, olopatadine reduces itchy and/or runny nose and sneezing.²⁸ Mometasone furoate, like other corticosteroids, possesses anti-inflammatory, vasoconstrictive, and antipruritic properties.¹⁷ Mometasone furoate crosses cellular membranes to repress inflammatory gene transcription either directly or by activating the transcription of anti-inflammatory factors. In vitro, mometasone furoate blocks the synthesis and release of interleukin-1, interleukin-6, and tumour necrosis factor alpha from CD4+ T cells,²⁹ and inhibits the production of T helper 2 cytokines, interleukin-4, and interleukin-5, from CD4+ T cells.³⁰ By blocking these pathways, the intranasal corticosteroid mometasone reduces SAR symptoms of nasal itching and congestion, sneezing, and rhinorrhea by inhibiting the release of inflammatory mediators.³⁰ As a monotherapy, mometasone has a well-documented safety profile with minimal systemic effects.³⁰ Mechanistically, olopatadine may trigger fast relief from the symptoms of SAR, while mometasone furoate may act to suppress the underlying allergic inflammatory reaction.^18,19

On September 21, 2022, olopatadine hydrochloride and mometasone furoate monohydrate received a Notice of Compliance from Health Canada for the symptomatic treatment of moderate to severe SAR and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.² The sponsor’s reimbursement request is in line with the Health Canada indication. Olopatadine-mometasone has not been previously reviewed in Canada. Olopatadine-mometasone received approval from the FDA in January 2022 for the treatment of symptoms of SAR in adults and pediatric patients aged 12 years and older.^31,32

The recommended dosage is 2 sprays (665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate per delivered dose) for patients who are aged 12 years and older, and 1 spray for patients aged 6 to 11 years in each nostril twice daily.²

Key characteristics of olopatadine-monohydrate and other treatments available for SAR are summarized in Table 5.

Table 5: Key Characteristics of Olopatadine-Mometasone and Main Comparators

AE = adverse event; AGEP = acute generalized exanthematous pustulosis; AR = allergic rhinitis; CNS = central nervous system; H1 = histamine-1; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PAR = perennial allergic rhinitis; SAR = seasonal allergic rhinitis.

^aHealth Canada–approved indication.

Sources: Product monographs.^2,33-42

Perspectives of Patients, Clinicians, and Drug Programs

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups. The full original patient input(s) received by the review team have been included in the Perspectives of Patients, Clinicians, and Drug Programs section of this report.

This review received patient group submissions from Asthma Canada and Allergy Quebec. Asthma Canada is a national charity focusing on improving the quality of life and health for people with asthma and respiratory allergies. Allergy Quebec is the main reference centre in Quebec for patients with food allergies and brings together allergists, nutritionists, pharmacists, institutions, and companies in the food sector.

Asthma Canada collected patient input using its 2024 Annual Asthma Survey from a total of 1,407 patients and caregivers. To gain more in-depth knowledge of the impact of AR on quality of life, Asthma Canada also conducted 2 one-on-one interviews with patients with AR who were selected at random from the participants who completed the AR section of the survey and provided their contact information. Allergy Quebec did not collect any input data from patients.

Both patient groups noted that AR can cause uncomfortable symptoms, including runny and/or itchy nose, nasal congestion, swollen and/or itchy eyes, headaches, sinus pain and/or pressure, and tiredness that negatively impact daily activities and quality of life. In total, 82% of the survey respondents indicated that the most difficult and/or frustrating aspect of living with AR is the physical symptoms. Patients stated that finding a solution and/or treatment to eliminate or significantly lessen the symptoms of AR would be important for them, in particular, elimination of rhinorrhea, relief of other symptoms, and more effective medications that do not trigger asthma flare-ups.

The patient groups noted that treatments for AR consist of prescription and nonprescription options, including corticosteroids, anticholinergics, oral and intranasal antihistamines, immunotherapy, and over-the-counter decongestants. Based on the survey data from Asthma Canada, just 43% of the participants reported that their current treatments can, or most of the time can, control their allergic symptoms, while 57% reported that current treatments do not control their symptoms. Based on the interview results from Asthma Canada, patient concerns included the lack of efficacy or lack of sustained efficacy, the undesired side effects (e.g., drowsiness, stuffy, or dry nose), and the cost and problems with accessing some antihistamines (e.g., due to lack of insurance coverage or availability at local pharmacies). No patients with experience using olopatadine-mometasone were reported by either patient group.

Clinician Input

Input From the Clinical Experts Consulted by the Review Team

All Canada’s Drug Agency review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of SAR in adult patients or pediatric patients.

Unmet Needs

According to the clinical experts consulted by the review team, the main goals of the management of moderate to severe SAR include alleviating symptoms, improving quality of life, and minimizing symptom exacerbations. The clinical experts consulted by the review team noted several unmet needs in the treatment of SAR:

• Not all patients respond adequately to currently available treatments, particularly intranasal corticosteroids and oral antihistamines, while some patients may experience only partial symptom relief.

• A patient’s condition can become refractory to current treatment options over time, e.g., due to an escalation of eosinophilic inflammation that does not respond to first-line treatment with antihistamines.

• There is a lack of treatment options that can modify the underlying disease mechanism of SAR. Allergen immunotherapy (e.g., sublingual immunotherapy) is currently the only treatment option that modifies the disease mechanism. Most treatments focus on symptom management rather than altering the disease progression.

• While current treatments aim to alleviate symptoms like nasal congestion and pruritis, there is a need for therapies that address broader outcomes, such as reducing the frequency and severity of exacerbations, improving sleep quality, and enhancing overall quality of life. The specific outcomes of importance may vary slightly between adults and younger patients, such as school attendance and social activities in children and adolescents.

• There is a need for treatment options that can offer better treatment tolerance. Some patients experience AEs with currently available treatments, such as nasal irritation or epistaxis with intranasal corticosteroids, or drowsiness with oral antihistamines. Younger patients may be more sensitive to side effects or have difficulty with medication administration, especially children, who may struggle with the proper administration of NSs or dislike the taste or smell of some oral and intranasal medications.

• The clinical experts consulted by the review team noted that most intranasal corticosteroids do not provide instant relief of symptoms, which may affect patients’ adherence. There is a need for treatment options that can improve treatment adherence.

• There is a need for more convenient formulations that enhance ease of use and patient acceptance, such as once-daily dosing options, user-friendly devices for NSs, or novel delivery systems.

Place in Therapy

According to the clinical experts consulted by the review team, olopatadine-mometasone can be used as a first-line or combination treatment option based on individual patient needs and treatment responses, by providing a dual-action therapy that combines an intranasal corticosteroid with an antihistamine. The clinical experts consulted by the review team noted that in clinical practice, intranasal corticosteroids alone are usually given to patients first because they can be given once daily and may be sufficient to treat symptoms. Intranasal corticosteroids with antihistamines are usually reserved for when intranasal corticosteroids alone are insufficient because the combination therapy is generally more costly, requires twice-daily administration, and may not be tolerated due to taste. However, the clinical experts consulted by the review team also noted that it is not necessary to trial monotherapy with an antihistamine or nasal corticosteroid before using olopatadine-mometasone. According to the clinical experts consulted by the review team, generally, 50% of the dose of intranasal corticosteroid is preferred for children aged between 6 and 12 years, and olopatadine-mometasone containing intranasal mometasone 25 mcg will allow clinicians to prescribe a more appropriate dose for children.

According to the clinical experts consulted by the review team, Dymista (fluticasone propionate 50 mcg plus azelastine 137 mcg NS) is already available in Canada, although it received a Do Not List recommendation for reimbursement in 2015. Dymista, like olopatadine-mometasone, requires twice-daily administration due to the duration of effect of the antihistamine.

Patient Population

According to the clinical experts consulted by the review team, the patients most suitable or most likely to respond to olopatadine-mometasone include the following:

• Patients who are experiencing moderate to severe symptoms of SAR, have had an inadequate response to monotherapy with intranasal corticosteroids or antihistamines, and require both anti-inflammatory (intranasal corticosteroids) and antihistaminic or mast cell–stabilizing effects to effectively manage their symptoms.

• Patients whose quality of life is significantly impacted by SAR symptoms, affecting daily activities, sleep, and overall well-being. Additionally, the clinical experts consulted by the review team noted that patients who want a quicker onset of action and struggle with treatment adherence or patients who are most troubled by eye symptoms may be suitable for olopatadine-mometasone.

According to the clinical experts consulted by the review team, the patients best suited for olopatadine-mometasone would be identified through a clinical evaluation and symptom assessment. The clinical experts consulted by the review team noted that assessment of symptom severity would occur by obtaining a patient history and conducting a physical examination. The clinical experts consulted by the review team also noted that a nasal endoscopy or rhinoscopy may help evaluate the degree of nasal inflammation or identify structural causes (e.g., septal deviation) that may be contributing to nasal inflammation, but is not essential to identify AR or stratify its severity. Furthermore, allergy testing, such as skin prick tests or specific IgE testing, can identify allergens triggering symptoms, but is not required specifically for initiation of olopatadine-mometasone. The clinical experts consulted by the review team noted some issues related to a diagnosis of SAR, particularly that underdiagnosis of AR may occur when symptoms are not fully explored or when seasonal triggers are not adequately considered, and symptoms of SAR can overlap with other conditions, such as nonallergic rhinitis or chronic sinusitis. A companion diagnostic test is not required for the use of olopatadine-mometasone.

According to the clinical experts consulted by the review team, patients least suitable for olopatadine-mometasone include those with mild symptoms of AR that are well controlled with monotherapy (either intranasal corticosteroids or antihistamines alone).

Assessing the Response Treatment

According to the clinical experts consulted by the review team, in clinical practice, determining treatment response involves assessing various outcomes that reflect improvements in symptom control and overall quality of life. The clinical experts consulted by the review team noted that the typical outcomes used to assess response include reductions in the frequency and severity of nasal and ocular symptoms, such as congestion, sneezing, itching, rhinorrhea, and eye redness or watering. The clinical experts consulted by the review team noted that the extent to which these symptoms interfere with daily activities, sleep patterns, and productivity is evaluated, with assessments conducted regularly, especially at the beginning of treatment and during peak allergy seasons, to ensure efficacy and to adjust therapy as needed. Per the clinical experts consulted for this review, the outcomes used in clinical practice are generally aligned with those used in clinical trials, which measure symptom scores, medication usage, and quality of life. However, in clinical practice, emphasis may be placed on patient-reported outcomes, such as subjective improvement in symptoms and the impact on daily living, which may not always be captured in trials.

According to the clinical experts consulted by the review team, a clinically meaningful response to treatment varies among individuals and may depend on the severity of initial symptoms and the patient’s expectations, while the threshold for a clinically meaningful response can vary among physicians based on their clinical experience, the patient population, and treatment goals. The 2 clinical experts consulted by the review team noted that at least a 50% improvement in baseline scores in terms of a reduction in symptom frequency or severity would be considered a clinically meaningful response, while a 20% improvement would be considered the threshold for clinical significance.

Discontinuing Treatment

The clinical experts consulted by the review team noted several situations when the discontinuation of olopatadine-mometasone should be considered:

• Lack of effectiveness: When there is persistence in or worsening of symptoms despite adherence to treatment. If the patient’s symptoms are not adequately controlled or continue to interfere significantly with daily activities despite optimized therapy, a re-evaluation of treatment effectiveness is warranted.

• AEs: When AEs (e.g., nasal irritation, epistaxis) are intolerable or persist despite management strategies. The frequency, severity, and impact of AEs on the patient’s quality of life should be assessed. If patients develop chronic rhinosinusitis with nasal polyposis, clinicians may want to increase the intranasal corticosteroid to the maximum dose (generally mometasone 100 mcg in each nostril twice daily). Although rare, patients may develop a septal perforation, which may be irritated by the intranasal corticosteroid.

• Patient preference or adherence: When a patient has difficulty with administration (e.g., improper technique when using an NS) or expresses dissatisfaction with treatment despite adequate symptom control, alternative therapeutic options should be discussed.

Prescribing Considerations

According to the clinical experts consulted by the review team, olopatadine-mometasone is suitable for treatment in various clinical settings, including community settings, outpatient clinics in hospitals, and specialty allergy clinics. In the community setting, primary care physicians can diagnose and initiate treatment for patients with SAR based on presenting symptoms and allergy history, as well as monitor treatment response through regular follow-up visits and adjust therapy as needed. Similarly, the clinical experts consulted by the review team noted that hospital outpatient clinics provide an appropriate environment for managing more complex cases or patients requiring specialist consultation. Although specialists such as allergists, immunologists, or otolaryngologists may offer additional expertise in managing severe or refractory cases of SAR, their involvement is not always required for routine diagnosis and management with olopatadine-mometasone.

Clinician Group Input

No clinician group input was received by the review team for this review.

Drug Program Input

The drug programs provide input on each drug being reviewed through the Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by the review team are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

AR = allergic rhinitis; b.i.d. = twice a day; CDEC = Canadian Drug Expert Committee; IgE = immunoglobulin E; NS = nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; pCPA = pan-Canadian Pharmaceutical Alliance; PAR = perennial allergic rhinitis; SAR = seasonal allergic rhinitis; vs. = versus.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of olopatadine-mometasone (665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate per dose, delivered by NS) for the symptomatic treatment of moderate to severe SAR and associated ocular symptoms in adults, adolescents, and children aged 6 years and older. The focus will be placed on comparing olopatadine-mometasone with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of olopatadine-mometasone is presented in 2 sections, with a critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor.

Of note, a long-term extension study that evaluated the long-term (52 weeks) safety, tolerability, and efficacy of olopatadine-mometasone in adults and adolescents (aged 12 years and older) with PAR was submitted by the sponsor. However, given that the Health Canada–approved indication and reimbursement request are for the treatment of SAR, the long-term study submitted by the sponsor was not considered relevant to this Clinical Review Report and has therefore not been summarized and appraised.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 3 pivotal, phase III, double-blind, RCTs (GSP301-301, GSP301-304, GSP301-305)

• 2 sponsor-submitted NMAs.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Three pivotal studies, GSP301-301, GSP301-304, and GSP301-305, all of which were conducted by the sponsor, met the inclusion criteria for the sponsor-submitted SLR. Characteristics of the included studies are summarized in Table 7.

Both the GSP301-301 and GSP301-304 trials were phase III randomized, double-blind, parallel-group studies evaluating the efficacy and safety of olopatadine-mometasone in adult and adolescent patients (aged 12 years and older) with SAR. Both studies consisted of 2 phases, a placebo run-in period (spanning 7 to 10 days from the screening visit to the randomization visit) and a treatment period (lasting 15 to 17 days from the randomization visit to the final treatment visit). The primary objective of both studies was to compare the efficacy of olopatadine-mometasone with placebo and the individual constituent monotherapies at the same dose in the same vehicle, and to assess the efficacy of these individual constituent monotherapies versus placebo over 14 days of study treatment.

The GSP301-301 study enrolled patients across 43 sites in the US. After completion of the placebo run-in period, 1,176 patients were randomized equally into 4 groups based on a computer-generated randomization scheme: 294 patients to olopatadine-mometasone, 294 patients to olopatadine hydrochloride NS, 294 patients to mometasone NS, and 294 patients to placebo NS.

The GSP301-304 study enrolled patients across 37 study sites in the US. After completion of the placebo run-in period, 1,180 patients were randomized to 4 treatment groups, with 302 patients assigned to olopatadine-mometasone, 297 patients to olopatadine hydrochloride NS, 294 patients to mometasone NS, and 287 patients to placebo NS.

GSP301-305 was a phase III double-blind, randomized, parallel-group, placebo-controlled study evaluating the use of olopatadine-mometasone in pediatric patients (aged ≥ 6 to < 12 years) with SAR. The GSP301-305 study comprised a single-blind placebo run-in period lasting 7 to 10 days from the screening visit to the randomization visit followed by a 14-day double-blind treatment period, with the final or discontinuation visit scheduled for day 15. Upon completion of the placebo run-in period, 446 patients were randomized to olopatadine-mometasone (N = 225) or placebo (N = 221). The primary objective of the GSP301-305 trial was to assess the efficacy of olopatadine-mometasone relative to placebo over 14 days of study treatment.

Table 7: Details of Studies Included in the Systematic Review

ADHD = attention-deficit/hyperactivity disorder; AR = allergic rhinitis; CYP3A4 = cytochrome P450 3A4; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total Ocular Symptom Score; mometasone NS = mometasone furoate nasal spray; NR = not reported; NS = nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PNSS = Physician-Assessed Nasal Symptom Score; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RCAT = Rhinitis Control Assessment Test; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SAR = seasonal allergic rhinitis.

^aOlopatadine hydrochloride NS is not available in Canada.

Sources: Sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²² Details included in the table are from the sponsor’s summary of clinical evidence.¹

Populations

Inclusion and Exclusion Criteria

The GSP301-301 trial enrolled male and female patients aged 12 years and older with a documented clinical history of SAR (for at least 2 years preceding the screening visit) with exacerbations (clinical evidence of active symptoms) during the spring allergy season (tree or grass pollen) or with a positive skin prick test result for relevant allergens (wheal diameter at least 5 mm greater than the negative control) during the fall or mountain cedar allergy seasons (e.g., ragweed pollen, mountain cedar pollen). At the screening visit, patients were required to demonstrate a minimum average morning (a.m.) and evening (p.m.) 12-hour rTNSS of 8 or higher out of 12, along with an a.m. congestion score of 2 or higher.

The GSP301-305 trial enrolled patients who were aged between 6 and 12 years with a clinical history of SAR for at least 2 years before screening, with exacerbations during the spring or fall allergy seasons for the relevant seasonal allergen (e.g., tree or grass pollen or ragweed pollen) and a positive skin prick test result (wheal diameter at least 5 mm greater than the negative control) consistent with their medical history of SAR. Patients were required to have a 12-hour rTNSS of 6 points or greater for the a.m. assessment at the screening visit.

Interventions

For both the GSP301-301 and GSP301-304 trials, the intervention group received intranasal olopatadine-mometasone (665 mcg of olopatadine hydrochloride and 25 mcg of mometasone furoate) for 14 days (2 sprays per nostril twice daily). For comparison,1 group was administered intranasal olopatadine hydrochloride (at a dose of 665 mcg), another group received mometasone NS (at a dose of 25 mcg), and a third group received placebo (vehicle comprising inactive ingredients identical to those used in the active treatments) for a period of 14 days (2 sprays per nostril twice daily). Of note, olopatadine hydrochloride NS is not relevant to this Reimbursement Review because it is currently unavailable in Canada; therefore, results for olopatadine hydrochloride are not presented in this Clinical Review Report.

For the GSP301-305 trial, the intervention group was administered intranasal olopatadine-mometasone (consisting of 665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate), with 1 spray administered in each nostril twice daily for a duration of 14 days. Placebo (vehicle) was used as the comparator, with 1 spray delivered in each nostril twice daily for the same 14-day period.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 8, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by the review team and the input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

Table 8: Outcomes Summarized From the Studies Included in the Systematic Review

iTNSS = instantaneous Total Nasal Symptom Score; NA = not applicable; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²² Details included in the table are from the sponsor’s summary of clinical evidence.¹

The following are descriptions of the efficacy and safety outcomes presented in studies GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ and appraised in this Clinical Review.

Efficacy Outcomes

Patient-Reported 12-Hour rTNSS and iTNSS

The rTNSS and iTNSS were assessed by scoring the severity of 4 nasal symptoms (i.e., rhinorrhea, sneezing, nasal congestion, and nasal itching) over the past 12 hours before the recording of the score (i.e., reflective) and just before each dosing (i.e., instantaneous), respectively.

Scores for each symptom ranged from 0 (no signs or symptoms evident) to 3 (severe signs or symptoms that are hard to tolerate). The overall rTNSS score was calculated as the sum of the self-reported severity scores for each of the 4 symptoms and ranged from 0 (no signs or symptoms evident) to 12 (severe signs or symptoms that are hard to tolerate). The a.m. assessment was performed before bathing, consumption of food or beverages, or strenuous activities. The p.m. assessment was performed approximately 12 hours after the a.m. assessment.

Patient-Reported 12-Hour rTOSS

The rTOSS was defined as the sum of 3 eye-related symptom scores: itching or burning eyes, tearing or watering eyes, and redness of eyes. Each symptom was scored on a scale of 0 to 3 with a maximum rTOSS score of 9. A higher score indicated worse symptoms.

Health-Related Quality of Life

Patient-reported HRQoL was measured by RQLQ(S) in the GSP301-301 and GSP301-304 trials and by PRQLQ in the GSP301-305 study. The measurement properties of the instruments are shown in Table 9.

Table 9: Summary of Outcome Measures and Their Measurement Properties

MID = minimal important difference; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; QoL = quality of life; RQLQ = Rhinoconjunctivitis Quality-of-Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; SAR = seasonal allergic rhinitis.

Harms Outcomes

The harms outcomes assessed in the GSP301-301, GSP301-304, and GSP301-305 trials mainly included TEAEs, TESAEs, withdrawal due to TEAEs, and deaths.

Statistical Analysis

Details on the statistical analysis of the efficacy end points in the GSP301-301, GSP301-304, and GSP301-305 trials are presented in Table 10.

GSP301-301 and GSP301-304 Trials

To evaluate the superiority of olopatadine-mometasone in comparison with placebo, a sample size of 279 patients per treatment group was determined to provide 94% power to detect a between–treatment group difference of 0.9 units (assuming an SD of 3.0) in the absolute change from baseline in average a.m. and p.m. 12-hour rTNSS over the 14-day treatment period (assuming a 2-sided alpha of 5%). Additionally, this sample size could afford a 94% power to detect a between–treatment group difference of 0.6 units (assuming an SD of 2.0) in the absolute change from baseline in average a.m. and p.m. 12-hour rTNSS over the same treatment period when comparing olopatadine-mometasone with each monotherapy (i.e., olopatadine hydrochloride NS or mometasone NS). Finally, 279 patients per treatment group could provide 90% power to detect a treatment difference between each monotherapy and placebo of 0.55 units (assuming an SD of 2.0) in the absolute change from baseline in average a.m. and p.m. 12-hour rTNSS over the 14-day treatment period.

Efficacy end points were analyzed utilizing a mixed model for repeated measures, which was adjusted for covariates, including treatment, site, baseline clinical measures, and study day as the within-patient effect, with the assumption that any missing data were missing at random. To adjust for multiple comparisons, a gatekeeping strategy was adopted for rTNSS, iTNSS, and rTOSS. Statistical significance was set at a P value of less than 0.05 for all analyses. The gatekeeping strategy for rTNSS and rTOSS is shown in Figure 1.

Figure 1: Gatekeeping Strategy in the GSP301-301 and GSP301-304 Trials

NS = nasal spray; vs = versus.

Note: GSP 301 in the figure refers to olopatadine hydrochloride and mometasone furoate nasal spray.

Source: Sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

GSP301-305 Trial

To assess the superiority of olopatadine-mometasone over placebo, a sample size of 382 patients was determined to provide 90% power to detect a between-group mean difference of 1.0 unit (assuming an SD of 3.0 and a 2-sided alpha of 5%) in the absolute change from baseline in average a.m. and p.m. 12-hour rTNSS over the 14-day treatment period.

Efficacy end points were analyzed utilizing a mixed model for repeated measures that was adjusted for covariates, including treatment, site, baseline clinical measures, and study day as the within-patient effect, with the assumption that any missing data were missing at random. No multiplicity adjustment was made.

Table 10: Statistical Analysis of Efficacy End Points for Included Studies

ANCOVA = analysis of covariance; iTNSS = instantaneous Total Nasal Symptom Score; MAR = missing at random; MMRM = mixed model for repeated measures; MNAR = missing not at random; NR = not reported; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score.

Sources: Clinical Study Reports for GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Analysis Populations

The analysis populations for the GSP301-301, GSP301-304, and GSP301-305 trials are summarized in Table 11.

Table 11: Analysis Populations for the GSP301-301, GSP301-304, and GSP301-305 Trials

FAS = full analysis set; iTNSS = instantaneous Total Nasal Symptom Score; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Protocol Amendments and Deviations

GSP301-301 Trial

In total, there were 3 versions of the clinical study protocol for the GSP301-301 trial. The original study protocol (version 1.0) was issued on October 26, 2015. Protocol version 2.0 and version 3.0 were issued on December 10, 2015, and January 25, 2016, respectively; all issue dates were before the start date for patient recruitment (i.e., March 2016). In summary, the main changes to the protocol included sample size increases and changes to the eligibility criteria, including the addition of various medical conditions (e.g., clinically significant respiratory tract malformations, nasal structural abnormalities).

During the randomized treatment period in the safety analysis set, the proportions of patients who had protocol deviations were similar across treatment groups: 15.9% (48 out of 302) in the olopatadine-mometasone group, 17.3% (51 out of 294) in the mometasone NS group, and 15.3% (44 out of 287) in the placebo group. The most commonly reported deviation was “outside visit window” (67 deviations in total: 17 in the olopatadine-mometasone group, 19 each in the olopatadine group and mometasone NS group, and 12 in the placebo group).

GSP301-304 Trial

There were 3 versions of the clinical study protocol for the GSP301-304 trial. The original study protocol (version 1.0) was issued on June 22, 2015, while protocol version 2.0 was issued on September 6, 2016, and protocol version 3.0 was issued on November 15, 2016. After the start of patient recruitment (i.e., August 2016), changes were made to the inclusion criteria to extend the recruitment period to include the season for mountain cedar pollen to meet the target randomization number.

During the randomized treatment period in the safety analysis set, the proportions of patients who had protocol deviations were generally similar across treatment groups: 21.8% (64 out of 294) in the olopatadine-mometasone group, 22.2% (65 out of 293) in the mometasone NS group, and 19.7% (58 out of 294) in the placebo group. The most commonly reported deviation was “other protocol deviation” (total of 148 deviations).

GSP301-305 Trial

There were 3 versions of the clinical study protocol for the GSP301-305 trial. The original study protocol (version 1.0) was issued on January 8, 2018. Protocol version 2.0 was issued on April 5, 2018, and protocol version 3.0 was issued on July 18, 2018. After the start of patient recruitment (i.e., March 2018), changes were made to clarify season-related information (i.e., spring and fall allergy seasons) for the study.

During the randomized treatment period in the safety analysis set, the proportion of patients who had protocol deviations was slightly higher in the olopatadine-mometasone group (25.8%; 58 out of 225), compared with the placebo group (22.2%; 49 out of 221). The most commonly reported protocol deviation was “assessment not performed per protocol” (44 deviations in the olopatadine-mometasone group versus 35 deviations in the placebo group).

Results

Patient Disposition

A summary of patient disposition in the GSP301-301, GSP301-304, and GSP301-305 trials is shown in Table 12.

In the GSP301-301 trial, 1,696 participants were screened and 1,180 were randomized. In the GSP301-304 trial, 1,808 participants were screened and 1,176 were randomized. In the GSP301-305 trial, 616 participants were screened and 446 were randomized. The reasons for screening failure were NR for all 3 trials. In the GSP301-301 trial, 4.3% of patients in the olopatadine-mometasone group, 3.83% of patients in the placebo group, and 3.74% of patients in the mometasone NS group discontinued from the study. In the GSP301-304 trial, 1.7% of patients in the olopatadine-mometasone group, 2.38% of patients in the mometasone NS group, and 3.4% of patients in the placebo group discontinued from the study. The proportion of patients who discontinued from the GSP301-305 trial was 4.44% for the olopatadine-mometasone group and 2.26% for the placebo group.

Baseline Characteristics

The baseline characteristics outlined in Table 13 are limited to those that were considered most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

Overall, the baseline demographic and disease characteristics were generally similar across treatment groups within each of the 3 trials (GSP301-301, GSP301-304, and GSP301-305).

The baseline demographic and disease characteristics were similar overall between the GSP301-301 and GSP301-304 trials. In the GSP301-301 trial, the mean age of the study population was 39.3 years (SD = 15.3 years). The majority of patients were female (64.6%) and white (77.5%). In the GSP301-304 trial, the mean age of the patients was 39.6 years (SD = 14.81 years); the majority of the trial population was female (62.9%) and white (81.6%).

In the GSP301-305 trial, the mean age of the study population was 8.7 years (SD = 1.7 years). There were slightly more males (56.0%) in the olopatadine-mometasone group, while in the placebo group, the percentages of males and females were similar (50.7% versus 49.3%). The majority of the trial population was white (> 76.5%).

Exposure to Study Treatments

For the GSP301-301 and GSP301-304 trials, treatment duration was 14 plus 2 days. Twenty-eight doses (twice a day for 14 days) was considered 100% adherence, 35 or more doses (i.e., beyond 17 days of treatment due to out-of-window visits) was considered an adherence rate of 125% or more, and 21 or fewer doses was considered less than 75% adherence. Thus, it was possible for patients to have a treatment adherence of greater than 100% and still be compliant with the protocol. In the safety analysis set of the GSP301-301 trial, an adherence rate of between 75% and 125% was achieved by 94.4% of patients in the olopatadine-mometasone group, 94.2% in the mometasone NS group, and 95.1% in the placebo group. In the GSP301-304 trial, an adherence rate of between 75% and 125% was achieved by 99.6% of patients in the olopatadine-mometasone group, 99.0% in the mometasone NS group, and 98.6% in the placebo group.

For the GSP301-305 trial, treatment duration was 14 days but could have been up to 17 days based on permitted windows for study visits. Therefore, 28 doses (i.e., twice a day for 14 days) was considered 100% adherence. It was possible for patients to have a treatment adherence of greater than 100% and still be compliant with the protocol. In the safety analysis set of the GSP301-305 trial, the proportions of patients achieving an adherence rate of between 75% and 100% or between 100% and 125% were 81.3% and 15.6% in the olopatadine-mometasone group, respectively, and 79.6% and 17.6% in the placebo group, respectively.

Table 12: Summary of Patient Disposition From the Studies Included in the Systematic Review

FAS = full analysis set; mometasone NS = mometasone furoate nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Table 13: Summary of Baseline Characteristics From Studies Included in the Systematic Review (Safety Analysis Set)

FAS = full analysis set; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total Ocular Symptom Score; mometasone NS = mometasone furoate nasal spray; NA = not applicable; NR = not reported; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PNSS = Physician-Assessed Nasal Symptom Score; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SD = standard deviation.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²²

Concomitant Medications and Subsequent Treatment

At the discretion of the investigator and in consultation with the sponsor, patients were allowed to use any concomitant medications that were not prohibited by the study protocol.

In the GSP301-301 trial, the number of patients who used concomitant medications was 63 in the olopatadine-mometasone group, 65 in the mometasone NS group, and 65 in the placebo group. Some of the frequently used concomitant medications included ibuprofen (12 in the olopatadine-mometasone group, 8 in the mometasone NS group, and 13 in the placebo group), albuterol (6 in the olopatadine-mometasone group, 7 in the mometasone NS group, and 3 in the placebo group), naproxen (3 in the olopatadine-mometasone group, 0 in the mometasone NS group, and 5 in the placebo group), multivitamin (3 in the olopatadine-mometasone group, 0 in the mometasone NS group, and 3 in the placebo group), levothyroxine (1 in the olopatadine-mometasone group, 3 in the mometasone NS group, and 1 in the placebo group), Tylenol (1 in the olopatadine-mometasone group, 2 in the mometasone NS group, and 2 in the placebo group), and metformin (0 in the olopatadine-mometasone group, 0 in the mometasone NS group, and 2 in the placebo group).

No concomitant medications–related information summarized at the treatment-arm level was available for the GSP301-304 and GSP301-305 trials. None of the 3 pivotal trials reported any data on any subsequent treatment used.

Efficacy

Key efficacy results in the FAS during the randomized period are presented in Table 14. Given that olopatadine hydrochloride NS is currently unavailable in Canada, it was not considered relevant to this Reimbursement Review; thus, results for olopatadine hydrochloride are not presented.

Table 14: Summary of Key Efficacy Results From Studies Included in the Systematic Review (FAS)

CI = confidence interval; FAS = full analysis set; iTNSS = instantaneous Total Nasal Symptom Score; LS = least squares; mometasone NS = mometasone furoate nasal spray; NA = not applicable; NR = not reported; NS = nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PRQLQ = Paediatric Rhinoconjunctivitis Quality of Life Questionnaire; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SD = standard deviation; SE = standard error.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²² Details included in the table are from the sponsor’s summary of clinical evidence.¹

Twelve-Hour rTNSS Over the 14-Day Treatment Period

GSP301-301 Trial

The mean baseline rTNSS score was 10.1 (SD = 1.2) in the olopatadine-mometasone group and 10.2 (SD = 1.2) in both the mometasone NS and placebo groups. The within-group LS mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −3.48 points (SE = NR) in the olopatadine-mometasone group, −3.09 points (SE = NR) in the mometasone NS group, and −2.50 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −0.98 points (95% CI, −1.38 to −0.57) between the olopatadine-mometasone group and the placebo group and −0.39 points (95% CI, −0.79 to 0.01) between the olopatadine-mometasone group and the mometasone NS group, with both point estimates of the LS mean difference favouring the olopatadine-mometasone group.

GSP301-304 Trial

The mean baseline rTNSS score was 10.09 (SD = 1.2) in the olopatadine-mometasone group, 10.2 (SD = 1.2) in the mometasone NS group, and 10.3 (SD = 1.2) in the placebo group. The within-group LS mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −3.52 points (SE = NR) in the olopatadine-mometasone group, −3.05 points (SE = NR) in the mometasone NS group, and −2.44 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −1.09 points (95% CI, −1.49 to −0.69) between the olopatadine-mometasone group and the placebo group and −0.47 points (95% CI, −0.86 to −0.08) between the olopatadine-mometasone group and the mometasone NS group; both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

GSP301-305 Trial

The mean baseline rTNSS score was 8.83 (SD = 1.4) in the olopatadine-mometasone group and 8.84 (SD = 1.7) in the placebo group. The within-group LS mean change from baseline in the 12-hour rTNSS over the 14-day treatment period showed an improvement in both treatment groups: −1.6 points (SE = 0.18) in the olopatadine-mometasone group and −2.2 points (SE = 0.17) in the placebo group.

The between-group LS mean difference in the 12-hour rTNSS over the 14-day treatment period was −0.6 points (95% CI, −0.9 to −0.2) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Twelve-Hour iTNSS Over the 14-Day Treatment Period

GSP301-301 Trial

The mean baseline iTNSS score was 9.2 (SD = 1.7) in the olopatadine-mometasone group and 9.3 (SD = 1.7) in both the mometasone NS and placebo groups. The within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −3.03 points (SE = NR) in the olopatadine-mometasone group, −2.67 points (SE = NR) in the mometasone NS group, and −2.10 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.93 points (95% CI, −1.28 to −0.58) between the olopatadine-mometasone group and the placebo group and −0.36 points (95% CI, −0.71 to −0.01) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

GSP301-304 Trial

The mean baseline iTNSS score was 9.17 (SD = 1.8) in the olopatadine-mometasone group, 9.42 (SD = 1.8) in the mometasone NS group, and 9.58 (SD = 1.8) in the placebo group. The within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −3.11 points (SE = NR) in the olopatadine-mometasone group, −2.60 points (SE = NR) in the mometasone NS group, and −2.16 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.94 points (95% CI, −1.32 to −0.56) between the olopatadine-mometasone group and the placebo group and −0.51 points (95% CI, −0.88 to −0.13) between the olopatadine-mometasone group and the mometasone NS group, with both point estimates of the LS mean difference favouring the olopatadine-mometasone group.

GSP301-305 Trial

The mean baseline iTNSS score was 7.89 (SD = 1.9) in the olopatadine-mometasone group and 7.82 (SD = 2.0) in the placebo group. The within-group LS mean change from baseline in the 12-hour iTNSS over the 14-day treatment period showed an improvement in both treatment groups: −1.1 points (SE = 0.17) in the olopatadine-mometasone group and −1.8 points (SE = 0.17) in the placebo group.

The between-group LS mean difference in the 12-hour iTNSS over the 14-day treatment period was −0.6 points (95% CI, −1.0 to −0.3) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Twelve-Hour rTOSS Over the 14-Day Treatment Period

GSP301-301 Trial

The mean baseline rTOSS score was 7.1 (SD = 1.4) in the olopatadine-mometasone group, 7.0 (SD = 1.5) in the mometasone NS group, and 7.2 (SD = 1.3) in the placebo group. The within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −2.23 points (SE = NR) in the olopatadine-mometasone group, −2.04 points (SE = NR) in the mometasone NS group, and −1.74 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.49 points (95% CI, −0.79 to −0.19) between the olopatadine-mometasone group and the placebo group and −0.19 points (95% CI, −0.49 to 0.11) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

GSP301-304 Trial

The mean baseline rTOSS score was 6.95 (SD = 1.48) in the olopatadine-mometasone group, 7.04 (SD = 1.49) in the mometasone NS group, and 7.21 (SD = 1.41) in the placebo group. The within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in all 3 treatment groups: −2.36 points (SE = NR) in the olopatadine-mometasone group, −2.01 points (SE = NR) in the mometasone NS group, and −1.84 points (SE = NR) in the placebo group.

The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.52 points (95% CI, −0.84 to −0.20) between the olopatadine-mometasone group and the placebo group and −0.35 points (−0.66 to −0.03) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

GSP301-305 Trial

The mean baseline rTOSS score was 3.84 (SD = 2.45) in the olopatadine-mometasone group and 3.59 (SD = 2.52) in the placebo group. The within-group LS mean change from baseline in the 12-hour rTOSS over the 14-day treatment period showed an improvement in both treatment groups: −0.6 points (SE = 0.13) in the olopatadine-mometasone group and −0.8 points (SE = 0.14) in the placebo group.

The between-group LS mean difference in the 12-hour rTOSS over the 14-day treatment period was −0.2 points (95% CI, −0.6 to 0.1) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

RQLQ(S) Overall Score on Day 15

GSP301-301 Trial

The mean baseline RQLQ(S) score was 4.0 (SD = 1.1) in the olopatadine-mometasone group and 3.9 (SD = 1.2) in both the mometasone NS and placebo groups. The within-group LS mean change from baseline in the RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: −1.54 points (SE = NR) in the olopatadine-mometasone group, −1.34 points (SE = NR) in the mometasone NS group, and −1.11 points (SE = NR) in the placebo group.

The between-group LS mean difference in the RQLQ(S) overall score at day 15 was −0.43 points (95% CI, −0.64 to −0.21) between the olopatadine-mometasone group and the placebo group and −0.20 points (95% CI, −0.41 to 0.02) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

GSP301-304 Trial

The mean baseline RQLQ(S) score was 3.96 (SD = 1.24) in the olopatadine-mometasone group, 4.04 (SD = 1.26) in the mometasone NS group, and 4.0 (SD = 1.24) in the placebo group. The within-group LS mean change from baseline in the RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: −1.67 points (SE = NR) in the olopatadine-mometasone group, −1.22 points (SE = NR) in the mometasone NS group, and −1.58 points (SE = NR) in the placebo group.

The between-group LS mean difference in the RQLQ(S) overall score at day 15 was −0.45 points (95% CI, −0.68 to −0.22) between the olopatadine-mometasone group and the placebo group and −0.09 points (95% CI, −0.32 to 0.14) between the olopatadine-mometasone group and the mometasone NS group, and both point estimates of the LS mean difference were in favour of the olopatadine-mometasone group.

PRQLQ Overall Score on Day 15

GSP301-305 Trial

The mean baseline PRQLQ score was 2.51 (SD = 1.08) in the olopatadine-mometasone group and 2.42 (SD = 1.0) in the placebo group. The within-group LS mean change from baseline in the PRQLQ overall score at day 15 showed an improvement in all 3 treatment groups: −0.8 points (SE = 0.08) in the olopatadine-mometasone group and −0.5 points (SE = 0.08) in the placebo group.

The between-group LS mean difference in the PRQLQ overall score at day 15 was −0.3 points (95% CI, −0.5 to −0.1) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.

Harms

Harms data from the GSP301-301, GSP301-304, and GSP301-305 trials are shown in Table 15.

Table 15: Summary of Harms Results From the Studies Included in the Systematic Review (Safety Analysis Set)

mometasone NS = mometasone furoate nasal spray; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.

^aReported in ≥ 2% of patients in any treatment group.

Sources: Clinical Study Reports for the GSP301-301,²⁰ GSP301-304,²¹ and GSP301-305²³ trials and the sponsor’s response to the June 26, 2024, request by Canada’s Drug Agency for additional information.²² Details included in the table are from the sponsor’s summary of clinical evidence.¹

Treatment-Emergent Adverse Events

GSP301-301 Trial

The proportion of patients experiencing TEAEs was 12.9% (39 out of 302) in the olopatadine-mometasone group, which was higher than in the mometasone NS group (7.1%; 21 out of 294) and in the placebo group (9.4%; 27 out of 287). The proportion of patients who had dysgeusia was 3.3% (10 out of 302) in the olopatadine-mometasone group, 0.7% (2 out of 287) in the placebo group, and 0% in the mometasone NS group. Headache occurred in 2.8% (8 out of 287) of the patients in the placebo group, higher than in the olopatadine-mometasone group (0.7%; 2 out of 302) and in the mometasone NS group (0.7%; 2 out of 294). Epistaxis was reported in 1.3% (4 out of 302) of the patients in the olopatadine-mometasone group, 0.7% (2 out of 294) of the patients in the mometasone NS group, and 0.3% (1 out of 287) of the patients in the placebo group.

GSP301-304 Trial

The proportion of patients experiencing TEAEs was 15.6% (46 out of 294) in the olopatadine-mometasone group, higher than in the mometasone NS group (9.6%; 28 out of 293) and in the placebo group (9.5%; 28 out of 294). Dysgeusia was reported in 3.7% (11 out of 294) of the patients in the olopatadine-mometasone group and in 0% of patients in both the mometasone NS and placebo groups. Headache occurred in 1.4% (4 out of 293) of the patients in the mometasone NS group, 0.7% (2 out of 294) of the patients in the placebo group, and 0% of patients in the olopatadine-mometasone group. The proportion of patients who had epistaxis was 0.7% (2 out of 294) in the olopatadine-mometasone group, 1.0% (3 out of 293) in the mometasone NS group, and 1.0% (3 out of 294) in the placebo group.

GSP301-305 Trial

The proportion of patients experiencing TEAEs was 12.0% (27 out of 225) in the olopatadine-mometasone group and 10.4% (23 out of 221) in the placebo group. The most common TEAE in the olopatadine-mometasone group was epistaxis (2.3%; 5 out of 225), while 0.9% (2 out of 221) of the patients in the placebo group had epistaxis. Dysgeusia were reported in 1.3% (3 out of 225) of the patients in the olopatadine-mometasone group and in 0% of patients in the placebo group. Headache occurred in 1.3% (3 out of 225) of the patients in the olopatadine-mometasone group and 0.5% (1 out of 221) of the patients in the placebo group.

Treatment-Emergent Serious Adverse Events

GSP301-301 Trial

Only 1 patient had a TESAE (0.3%) in the GSP301-301 trial, which was 1 spontaneous abortion in the olopatadine-mometasone group.

GSP301-304 Trial

No patients had a TESAE in the olopatadine-mometasone group. One patient in the mometasone NS group (0.3%) had 1 TESAE (i.e., peritonsillar abscess), and 1 patient in the placebo group (0.3%) had 3 TESAEs (1 instance each of osteomyelitis, syncope, and foot fracture).

GSP301-305 Trial

There was only 1 TESAE (i.e., meningitis), which was reported in 1 patient (0.5%) in the placebo group.

Withdrawals Due to TEAEs

GSP301-301 Trial

No patients withdrew due to TEAEs in the olopatadine-mometasone group compared with 4 in the mometasone NS group and 1 in the placebo group. The specific reasons for withdrawal were NR.

GSP301-304 Trial

No patients withdrew due to TEAEs in the olopatadine-mometasone group or in the mometasone NS group. One patient (0.3%) in the placebo group discontinued due to a foot fracture.

GSP301-305 Trial

There were 4 patients (1.8%) who withdrew due to TEAEs (1 instance each of conjunctivitis, acute otitis media, and sinusitis, and 1 upper respiratory tract infection) in the olopatadine-mometasone group and 1 patient (0.5%) in the placebo group who withdrew due to otitis media.

Mortality

No deaths were reported in the GSP301-301, GSP301-304, or GSP301-305 trials.

Critical Appraisal

Internal Validity

This Clinical Review Report assesses 3 pivotal studies submitted by the sponsor, including 2 phase III RCTs (i.e., GSP301-301 and GSP301-304) in adolescents and adults (aged 12 years and older) with SAR, and 1 phase III RCT (i.e., GSP301-305) in children (aged ≥ 6 to < 12 years) with SAR. In the GSP301-301 trial, 1,696 participants were screened and 1,180 were randomized. In the GSP301-304 trial, 1,808 participants were screened and 1,176 were randomized. In the GSP301-305 trial, 616 participants were screened and 446 were randomized. None of the 3 trials reported the reasons for screening failure. All 3 pivotal trials used a computer-generated randomization scheme that was reviewed and approved by a statistician. Information on allocation concealment was unclear for the GSP301-301 and GSP301-304 trials, whereas central randomization was performed for the GSP301-305 study, which was considered adequate to conceal allocation. The baseline characteristics were generally balanced across treatment groups within each of the 3 pivotal trials. Consequently, it was determined that the overall risk of bias arising from the randomization process was low.

All 3 pivotal trials adopted a double-blind design, which masked the trial participants and trial personnel. Blinding was achieved by packaging the active products and placebo in identical bottles and outer cartons for all 3 pivotal trials. The risk of performance bias due to the awareness of treatment assignment was considered low by the review team. An adherence rate of between 75% and 125% (i.e., from twice a day for 14 days to twice a day for up to 17 days) was achieved by more than 90% of the patients in each treatment group, which the clinical experts considered to be higher than clinical practice. The clinical experts consulted by the review team considered the use of concomitant medications generally appropriate. There were no major concerns with respect to protocol amendments in any of the 3 pivotal trials.

The risk of bias due to missing outcome data was determined to be low for all 3 pivotal trials. Based on the patient disposition information, a small proportion of patients in each treatment group of the 3 pivotal trials discontinued from the study for various reasons (e.g., loss to follow-up, withdrawal by patients, nonadherence). In all 3 pivotal trials, analyses in the per-protocol analysis set, which excluded patients who had not adhered to the study protocol (defined as a major protocol violation), showed an LS mean difference in the rTNSS similar to that in the FAS. Moreover, the mixed model for repeated measures used in the primary analysis assumed the data missing were missing at random. The GSP301-301 and GSP301-304 studies conducted sensitivity analyses for the rTNSS using the jump-to-reference approach and/or tipping-point approach, which assumed the data missing were missing not at random. According to the study investigators, the results of these sensitivity analyses were in agreement with the primary analysis; however, the results were NR and could not be validated, although the small amount of missing data did not raise concerns for this assumption.

The patient-reported symptom scores evaluated in the pivotal studies included rTNSS (primary efficacy end point), iTNSS, and rTOSS. The definitions of these symptom scores were consistent across the 3 pivotal trials and considered accurate by the clinical experts consulted by the review team. However, because reflective and instantaneous symptom scales were designed primarily for assessment in adults, young children might need the assistance of a proxy to assess and report the severity of their symptoms. In the GSP301-305 trial, children assessed their symptoms with the assistance of their parents, guardians, or caregivers as needed. Inconsistency between children-reported symptom severity and proxy-reported symptom severity has been reported, where children with asthma, rhinitis, or eczema tended to report more symptoms than their parents⁵⁵ and, with an increase in the extent of child self-rating, there is a greater treatment difference between intervention and placebo, favouring the intervention.⁵⁶ However, the GSP301-305 trial did not conduct a subgroup analysis of rater difference for any efficacy outcomes. As a result, the possibility of underestimating the treatment difference between olopatadine-mometasone and placebo due to the assistance of a proxy remains unclear for the GSP301-305 trial.

Lastly, a gatekeeping strategy to adjust for multiplicity was used for the primary (rTNSS), and secondary outcomes (iTNSS and rTOSS) in the GSP301-301 and GSP301-304 trials; however, multiplicity was not adjusted for the secondary outcomes of RQLQ(S) in these 2 trials. In the GSP301-305 trial, adjustment for multiplicity was not carried out for any outcome, so results should be considered with respect to the potential for type I error.

External Validity

The Health Canada–approved indication of olopatadine-mometasone is for patients with moderate to severe SAR; however, none of the 3 pivotal trials explicitly used the term “moderate to severe” to describe disease severity in the trial eligibility criteria. Instead, in the GSP301-301 and GSP301-304 trials, severity was defined as patients with an rTNSS of 8 or greater (out of a possible 12 points) and a congestion score of 2 or greater for the a.m. assessment at the screening visit. In the GSP301-305 trial, severity was defined as patients with an rTNSS of 6 or greater (out of a possible 12 points) and a congestion score of 2 or greater for the a.m. assessment at the screening visit. According to the clinical experts consulted by the review team, the aforementioned symptom scores thresholds correctly reflect “moderate to severe” disease severity and were appropriate in the clinical trial setting to define patients with moderate to severe SAR. However, the clinical experts also noted that in the clinical setting, these symptom score thresholds are typically not required to determine a patient’s disease severity. Instead, determination of disease severity relies on a clinician’s judgment based on the extent to which patients are impacted by their symptoms. The clinical experts noted there are patients with SAR who do not meet these minimum threshold scores for moderate to severe disease but could still benefit from olopatadine-mometasone if they are seriously impacted by their symptoms.

According to the clinical experts consulted by the review team, the eligibility criteria of all 3 pivotal trials were, in general, appropriate from the perspective of selecting patients for clinical trials. However, the clinical experts noted that from the perspective of real-world clinical practice, the exclusion criteria of the 3 pivotal trials were restrictive. For instance, per the clinical experts, patients with nasal structural abnormalities and/or patients with a history of significant rhinitis medicamentosa were excluded while, in clinical practice, these patients might benefit from olopatadine-mometasone. Despite these potential concerns, the experts consulted by the review team noted that the trial eligibility criteria were still reflective of the patients they would see in the real world and may be generalized to a broader population.

The clinical experts consulted by the review team noted that the dose and duration of treatments used in the 3 pivotal trials were, in general, appropriate and adequate in the clinical trial setting. However, according to the clinical experts, the treatment duration used in the pivotal trials might not be reflective of the duration of treatment in the real-world setting, where patients are often given treatment for a longer period. The clinical experts consulted by the review team noted that patient adherence to treatment in all 3 pivotal trials was higher than they would expect to see in the real world, which may overestimate the treatment effect that would be observed in a real-world setting.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform the expert committee deliberations by Canada’s Drug Agency, and a final certainty rating was determined as outlined by the GRADE Working Group:^57,58

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, the evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty-of-evidence assessment for the rTNSS, iTNSS, rTOSS, RQLQ(S), and PRQLQ were set according to the presence of an important effect based on thresholds agreed upon by the clinical experts consulted by the review team for this review. For harms outcomes, the certainty of evidence was summarized narratively.

For the GRADE assessments, the findings from the GSP301-301 and GSP301-304 trials were considered together and summarized narratively per outcome and per comparison because these studies were similar in population, interventions, design, and outcome measures. The findings from the GSP301-305 trial were assessed individually because that trial had a child population (aged ≥ 6 years and < 12 years), while the GSP301-301 and GSP301-304 trials had an adolescent and adult population (aged 12 years and older).

Results of GRADE Assessments

Olopatadine-Mometasone Versus Placebo

Table 2 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for adolescent and adult patients (aged 12 years and older) with SAR.

Table 4 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for children (aged ≥ 6 to < 12 years) with SAR.

Olopatadine-Mometasone Versus Mometasone NS

Table 3 presents the GRADE summary of findings for olopatadine-mometasone versus mometasone NS for adolescent and adult patients (aged 12 years and older) with SAR.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Long-term extension studies of olopatadine-mometasone in moderate to severe SAR were not available.

Instead, the sponsor submitted a double-blind, randomized, parallel-group study (NCT02709538)^59,60 to evaluate the long-term (52 weeks) safety, tolerability, and efficacy outcomes of olopatadine-mometasone in adults and adolescents (aged 12 years and older) with PAR, a condition that was not included in either the Health Canada–approved indication for olopatadine-mometasone or in the reimbursement request.¹ Therefore, the long-term extension study was considered not relevant to this review and was not appraised. A brief description of the sponsor-submitted long-term extension study follows.

In NCT02709538, a total of 593 patients were randomized 4:1:1 to olopatadine-mometasone (N = 393), which has a pH value of 3.7, or to a placebo with a pH value of either 3.7 (N = 99) or 7.0 (N = 101). The overall TEAE rates at week 52 were numerically greater in the placebo pH 7.0 group than in the other 2 treatment groups.¹ A total of 326 patients were treated with olopatadine-mometasone for 6 months, and 250 patients were treated with olopatadine-mometasone for 1 year.² The incidence of TEAEs reported in 2% or more of patients was greater among the patients in the placebo pH 3.7 group (i.e., matches the pH of olopatadine-mometasone) compared with the patients treated with olopatadine-mometasone. These TEAEs were upper respiratory tract infection (6.4% in the olopatadine-mometasone group versus 6.1% in the placebo pH 3.7 group), epistaxis (4.6% versus 2.0%), headache (4.1% versus 3.0%), nasal discomfort (2.8% versus 2.0%), viral upper respiratory tract infection (2.3% versus 2.0%), urinary tract infection (2.3% versus 2.0%), cough (2.3% versus 2.0%), and dysgeusia (2.0% versus 0).^2,61 At week 52, a higher proportion of patients in the placebo pH 3.7 group reported nasopharyngitis (5.1%) compared with the olopatadine-mometasone group (3.1%).^1,61 Over 52 weeks, serious AEs were experienced by 11 patients, 7 in the olopatadine-mometasone group (1.8%), 2 in the placebo pH 3.7 group (2.0%), and 2 in the placebo pH 7.0 group (2.0%).^1,61 No deaths occurred during the study.^1,61

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

The pivotal trials submitted by the sponsor (i.e., GSP301-301, GSP301-304, and GSP301-305) provided head-to-head comparisons between olopatadine-mometasone versus placebo, olopatadine hydrochloride NS, and mometasone NS. However, the relative efficacy between olopatadine-mometasone and the general class of corticosteroids and antihistamines is unclear. Therefore, an ITC is warranted to address this evidence gap.

Description of the Indirect Comparisons

Two ITCs,⁶² both of which were NMAs, were submitted by the sponsor. According to the clinical experts consulted by the sponsor, it was not appropriate to combine studies in adolescent and adult patients (i.e., aged 12 years and older) with studies in children (i.e., aged ≥ 6 to < 12 years). Therefore, the sponsor conducted NMAs for 2 age groups separately.

The NMA for patients with SAR aged 12 years and older assessed the efficacy of olopatadine-mometasone relative to placebo, intranasal corticosteroids, and oral antihistamines, while the NMA for patients with SAR aged from 6 years to younger than 12 years compared olopatadine-mometasone relative to placebo and intranasal corticosteroids.

Indirect Treatment Comparison Design

Objectives

The objectives of the 2 sponsor-submitted NMAs were to assess the relative efficacy for olopatadine-mometasone versus the existing relevant comparators in patients with SAR aged 12 years and older and in patients with SAR aged from 6 years to younger than 12 years, respectively. Of note, descriptions in this section apply to both NMAs, unless specified otherwise.

Study Selection Methods

The criteria for study selection and the methods for the 2 ITCs submitted by the sponsor are shown in Table 16. An SLR conducted by the sponsor served as the evidence base. Studies eligible for the ITCs were identified according to the eligibility criteria, as outlined in Table 16. The literature searches, last updated on March 24, 2024, were conducted in multiple electronic databases, conference proceedings, and trial registries. Searches of relevant systematic reviews and meta-analyses, including NMAs, were performed to ensure the initial searches captured all relevant clinical studies. The study screening and selection process was conducted by 2 independent reviewers, with disagreement resolved by consultation with a third reviewer. Data were extracted by 1 reviewer and verified by a second reviewer. A risk-of-bias assessment for each included study was carried out using the revised Cochrane risk-of-bias tool.⁶³

ITC Analysis Methods

The details with respect to the analysis methods for the sponsor-submitted ITCs are shown in Table 17.

Table 16: Study Selection Criteria and Methods for the ITCs Submitted by the Sponsor

IQR = interquartile range; ITC = indirect treatment comparison; NMA = network meta-analysis; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; SAR = seasonal allergic rhinitis; SD = standard deviation; SE = standard error; SLR = systematic literature review; TNSS = Total Nasal Symptom Score.

Sources: Sponsor-submitted ITCs.⁶² Details included in the table are from the sponsor’s summary of clinical evidence.¹

Table 17: Analysis Methods for the Sponsor-Submitted ITCs

DIC = deviance information criterion; FE = fixed effects; ITC = indirect treatment comparison; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total ocular symptom scores; LS = least squares; NMA = network meta-analysis; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; PNSS = Physician-Assessed Nasal Symptom Score; RCT = randomized controlled trial; RE = random effects; RM = ratio of means; RQLQ = Rhinoconjunctivitis Quality-of-Life Questionnaire; rTNSS = reflective Total Nasal Symptom Score; rTOSS = Reflective Total Ocular Symptom Score; SD = standard deviation; SLR = systematic literature review; TNSS = Total Nasal Symptom Score.

Sources: Sponsor-submitted ITCs.⁶² Details included in the table are from the sponsor’s summary of clinical evidence.¹

Results of ITC in Patients Aged 12 Years and Older

Summary of Included Studies

In total, 13 studies were included in the ITC for patients aged 12 years and older.^46,47,67-77 The characteristics of the 13 included studies are presented in Table 18, and the assessment of potential heterogeneity is shown in Table 19.

The risk of bias of the 13 RCTs included in the ITC for patients aged 12 years and older was assessed using the revised Cochrane risk-of-bias tool (i.e., RoB 2). The overall risk of bias was determined to be low for 3 included studies,^67,75,76 and there were some concerns of bias for 10 included studies.^{46,47,68-74,77} The concerns for the 10 included RCTs arose mainly from the risk of bias in the randomization process.

Table 18: Characteristics of the Included Studies in the Sponsor-Submitted ITC for Patients Aged 12 Years and Older

AE = adverse event; ITC = indirect treatment comparison; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total Ocular Symptom Score; LS = least squares; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; TNSS = Total Nasal Symptom Score; TOSS = Total Ocular Symptom Score.

Sources: Sponsor-submitted ITCs.⁶²

Table 19: Assessment of Homogeneity of the Sponsor-Submitted ITC for Patients Aged 12 Years and Older

ITC = indirect treatment comparison; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total Ocular Symptom Score; LS = least squares; PNSS = Physician-Assessed Nasal Symptom Score; RCT = randomized controlled trial; RQLQ(S) = Rhinoconjunctivitis Quality-of-Life Questionnaire – Standardized Activities; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SAR = seasonal allergic rhinitis; SD = standard deviation.

Source: Sponsor-submitted ITC.⁶²

Results

Twelve-Hour rTNSS

The base-case network diagram for the ITC for patients aged 12 years and older is presented in Figure 2.

Figure 2: Network Diagram for the Sponsor-Submitted ITC for Patients Aged 12 Years and Older (Base-Case Analysis)

ITC = indirect treatment comparison.

Source: Sponsor-submitted ITCs.⁶²

Both the fixed-effects (FE) and random-effects (RE) models were examined. The deviance information criterion (DIC) for the FE model was 82.60, while the DIC for the RE model was 63.15. The RE model was considered by the investigators to be a better fit than the FE model in the sponsor-submitted ITC; therefore, results from this model were used as the primary results. The results generated from the RE model, presented in Table 20, illustrate the estimated relative effects (mean or LS mean difference in symptom scores between the treatments) together with the 95% CrI. Negative values indicated a reduction in the Total Nasal Symptom Score (TNSS), which suggests that a treatment is more effective than its comparator.

In the base-case analysis, the mean or LS mean difference in the 12-hour rTNSS was −1.26 points (95% CrI, −1.86 to −0.67) between the olopatadine-mometasone and placebo arms, −0.27 points (95% CrI, −0.87, 0.33) between the olopatadine-mometasone and intranasal corticosteroids arms, and −0.91 points (95% CrI, −1.91 to 0.06) between the olopatadine-mometasone and oral antihistamine arms. Results from the sensitivity analyses were generally consistent with the results in the base-case analysis.

Table 20: Network Estimates for 12-Hour rTNSS (Patients Aged 12 Years and Older, RE Model)

CrI = credible interval; LS = least squares; NA = not applicable; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RE = random effects; rTNSS = reflective Total Nasal Symptom Score; SE = standard error; vs. = versus.

Source: Sponsor-submitted indirect treatment comparison.⁶²

Results of the ITC in Patients Aged From 6 Years to Younger Than 12 Years

Summary of Included Studies

In total, 4 studies were included in the ITC for children (aged ≥ 6 years and < 12 years).^48,78-80 The characteristics of the 4 included studies are presented in Table 21.

The risk of bias of the 4 RCTs included in the ITC for patients aged from 6 years to younger than 12 years was assessed using the revised Cochrane risk-of-bias tool (i.e., RoB 2). All 4 included RCTs^48,78-80 were rated as having some concerns, mainly deriving from the randomization process.

Table 21: Characteristics of Included Studies in the Sponsor-Submitted ITC for Patients Aged 6 Years to Younger Than 12 Years

CFB = change from baseline; ITC = indirect treatment comparison; LS = least squares; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; TNSS = Total Nasal Symptom Score.

Source: Sponsor-submitted ITC.⁶²

Table 22: Assessment of Homogeneity of the Sponsor-Submitted ITC for Patients Aged 6 Years to Younger Than 12 Years

ITC = indirect treatment comparison; iTNSS = instantaneous Total Nasal Symptom Score; iTOSS = instantaneous Total Ocular Symptom Score; LS = least squares; PNSS = Physician-Assessed Nasal Symptom Score; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; SAR = seasonal allergic rhinitis; SD = standard deviation; vs. = versus.

Source: Sponsor-submitted ITC.⁶²

Results

Twelve-Hour rTNSS

The base-case network diagram for the ITC for children (aged ≥ 6 to < 12 years) is presented in Figure 3.

Figure 3: Network Diagram for the Sponsor-Submitted ITC for Patients Aged 6 Years to Younger Than 12 Years (Base-Case Analysis)

ITC = indirect treatment comparison.

Sources: Sponsor-submitted ITCs.⁶²

The DIC for the FE model was 21.47, while the DIC for the RE model was 22.51. The FE model was considered by the investigators to be a better fit than the RE model in the sponsor-submitted ITC; therefore, results from this model were presented as the primary results for this comparison. The results generated from the FE model are presented in Table 23 and illustrate the estimated relative effects (mean or LS mean difference in symptom scores between the treatments) together with the 95% CrI. Negative values indicate a reduction in the TNSS, which suggests that a treatment is more effective than its comparator.

In the base-case analysis, the mean or LS mean difference in the 12-hour rTNSS was −1.21 points (95% CrI, −1.86 to −0.56) between the olopatadine-mometasone and placebo arms and −0.94 points (95% CrI, −1.63 to −0.26) between the olopatadine-mometasone and intranasal corticosteroids arms. The mean or LS mean difference in the 12-hour rTNSS yielded by the RE model was −1.21 points (95% CrI, −2.03 to −0.39) between the olopatadine-mometasone and placebo arms and −0.91 points (95% CrI, −1.76 to −0.01) between the olopatadine-mometasone and intranasal corticosteroids arms.

Table 23: Network Estimates for the 12-Hour rTNSS (Patients Aged 6 Years to Younger Than 12 Years, FE Model)

CrI = credible interval; FE = fixed effects; LS = least squares; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; rTNSS = reflective Total Nasal Symptom Score; vs. = versus.

Source: Sponsor-submitted indirect treatment comparison.⁶²

Critical Appraisal of the 2 NMAs Submitted by the Sponsor

Two NMAs were submitted by the sponsor: 1 targeting patients with SAR aged 12 years and older (referred to as the adolescents and adults NMA) that assessed the efficacy of olopatadine-mometasone compared with placebo, intranasal corticosteroids, and oral antihistamines, and 1 targeting patients with SAR aged 6 (inclusive) to younger than 12 years (referred to as the children NMA) that compared olopatadine-mometasone relative to placebo and intranasal corticosteroids.

The adolescents and adults NMA and the children NMA were based on 13 and 4 RCTs, respectively, and were identified from a sponsor-conducted SLR. The literature search for the SLR, which involved multiple electronic databases, clinical trial registries, conference proceedings, and reference lists of key systematic reviews and meta-analyses existing in the literature, was considered appropriate. Errors in the study selection and data extraction processes were minimized by carrying out the processes in duplicate. The risk of bias in the individual RCTs included in the NMAs was assessed using the revised Cochrane risk-of-bias tool (i.e., RoB 2).⁶³ There were some concerns regarding the randomization process for 10 out of 13 studies in the adolescents and adults NMA and for all 4 studies included in the children NMA, which might have introduced some uncertainty in the NMA estimates.

Both NMAs defined the review questions (i.e., population, intervention, comparator, outcomes, and study design) a priori. With respect to the comparators in the SLR protocol, the sponsor listed several active comparators under 2 drug classes: intranasal corticosteroids and oral antihistamines. The clinical experts consulted by the review team noted that some relevant comparators were missing from the 2 classes in the protocol. For instance, fluticasone furoate (approved by Health Canada for the treatment of the symptoms of SAR in patients aged 2 years and older), which is widely used or prescribed to reduce nasal inflammation and associated symptoms, was missing from intranasal corticosteroids. Bilastine (approved by Health Canada for the symptomatic relief of nasal and non-nasal symptoms of SAR in patients aged 4 years and older with a body weight of at least 16 kg) and rupatadine fumarate (approved by Health Canada for the symptomatic relief of nasal and non-nasal symptoms of SAR in patients aged 2 years and older), both of which can be used in patients with moderate to severe SAR, were missing from the oral antihistamines in the SLR protocol. The ITC report did not provide rationales for why these comparators were not included. Yet, missing relevant comparators from the SLR protocol might have resulted in missing evidence in the subsequent NMAs, although the impact of this potential bias remains unknown. In addition, there is a possibility that missing comparators may jeopardize the generalizability of the NMA results to these missing comparator therapies.

The network of the adolescents and adults NMA comprised 4 nodes, representing olopatadine-mometasone, intranasal corticosteroids, oral antihistamines, and placebo. The network of the children NMA comprised 3 nodes, which represented olopatadine-mometasone, intranasal corticosteroids, and placebo. The individual treatments identified from the included studies were categorized into corresponding nodes. The sponsor assumed that individual drugs in the same drug class were equivalent in terms of clinical efficacy (intraclass clinical equivalency), which was considered reasonable overall by the clinical experts consulted by the review team. However, it was noted that within some nodes, there were only 1 or 2 individual drugs included due to a lack of eligible studies, which was beyond the sponsor’s control. For instance, only loratadine was available and included in the oral antihistamine node in the adolescents and adults NMA, while other drugs specified in the protocol, such as cetirizine, desloratadine, and fexofenadine, were not. In the children’s NMA, the intranasal corticosteroid node included only mometasone and ciclesonide. Despite the assumption of intraclass clinical equivalency being reasonable, there was concern and associated uncertainty regarding whether only 1 or 2 individual therapies would properly represent the corresponding drug class in terms of efficacy. Thus, the interpretation of the efficacy of olopatadine-mometasone relative to the intranasal corticosteroid class and to the oral antihistamine class should be made with caution.

Out of 4 included studies in the NMA for children, 3 studies had multiple treatment arms that involved different doses of the same treatment. For instance, in Berger (2008),⁷⁸ patients with SAR were randomized to once-daily ciclesonide 100 mcg or 200 mcg or placebo for 2 weeks, while in NCT01458275,⁷⁹ patients received once-daily ciclesonide nasal aerosol 37 mcg or 74 mcg or placebo for 2 weeks. In the sponsor-submitted NMA report, no information was provided on which dosage groups of ciclesonide were selected to generate the NMA treatment estimates. In addition, the clinical experts consulted by the review team noted the large variance between the dose of ciclesonide (i.e., 100 mcg or 200 mcg once daily for 2 weeks) used in Berger (2008)⁷⁸ and the dose (i.e., 37 mcg or 74 mcg once daily for 2 weeks) used in NCT01458275.⁷⁹ As a result, this limitation represents an additional source of uncertainty in the treatment effects estimates for the children NMA.

The clinical experts consulted by the review team identified several patient and disease characteristics as potential sources of heterogeneity that might bias the NMA estimates. Some of these characteristics (i.e., age, sex, disease duration, baseline symptom scores, comorbidity) were examined by the sponsor in both the adolescents and adults NMA and the children NMA by the sponsor. In general, the clinical experts consulted by the review team agreed with the sponsor’s evaluation and identified no serious heterogeneity arising from the aforementioned patient and disease characteristics. However, the clinical experts consulted by the review team also noted some patient and disease characteristics that might be potential sources of heterogeneity were missing from the sponsor-conducted NMAs, including urban versus rural living conditions, genetic predisposition, family history of atopic diseases, and smoking or vaping status. Thus, some uncertainty concerning the results of the NMA is warranted due to these potential sources of heterogeneity; however, the inclusion of these variables was beyond the sponsor’s control, given the limited data available in the included studies.

The individual studies included in the adolescents and adults NMA and the children NMA reported TNSS, rTNSS, and 12-hour TNSS. Both NMAs used 12-hour rTNSS as the efficacy end point and assumed that TNSS and rTNSS could be considered equivalent to the average 12-hour rTNSS. The clinical experts consulted by the review team determined that this assumption was acceptable.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Discussion

Summary of Available Evidence

Three sponsor-conducted pivotal studies, GSP301-301, GSP301-304, and GSP301-305, were included in this review. Both GSP301-301 (N = 1,176) and GSP301-304 (N = 1,180) were phase III, double-blind RCTs that enrolled adolescent and adult patients (aged 12 years and older) with SAR. The primary objective of the GSP301-301 and GSP301-304 trials was to compare the efficacy of olopatadine-mometasone with placebo and the individual constituent monotherapies (i.e., olopatadine hydrochloride NS and mometasone NS) at the same dose in the same vehicle, and to assess the efficacy of olopatadine hydrochloride NS and mometasone NS versus placebo over 14 days of study treatment. Of note, olopatadine hydrochloride NS is currently unavailable in Canada and therefore not relevant to this Reimbursement Review. As such, results comparing olopatadine-mometasone with olopatadine hydrochloride NS are not presented in this report. The GSP301-305 trial (N = 446) was a phase III, double-blind, RCT investigating the efficacy and safety of olopatadine-mometasone compared with placebo over 14 days in children (aged ≥ 6 to < 12 years) with SAR. The primary end point of all 3 pivotal trials was change from baseline in the patient-reported 12-hour rTNSS. The secondary efficacy and safety outcomes reported in the 3 pivotal trials included change from baseline in the patient-reported 12-hour iTNSS, patient-reported 12-hour rTOSS, and harms (i.e., TEAEs, TESAEs, withdrawals, and deaths). HRQoL was evaluated in the GSP301-301 and GSP301-304 trials via the RQLQ(S), while the GSP301-305 trial used the PRQLQ. All 3 pivotal trials were completed.

The mean age of patients in the GSP301-301 and GSP301-304 trials was 39.3 years (SD = 15.3 years) and 39.6 years (SD = 14.81 years), while the mean age in the GSP301-305 trial was 8.7 years (SD = 1.7 years). In the GSP301-301 and GSP301-304 trials, most patients were female (64.6% and 62.9%, respectively). In the GSP301-305 trial, there were slightly more males (56.0%) in the olopatadine-mometasone group while, in the placebo group, the proportions of male and female patients were similar (50.7% versus 49.3%). In the GSP301-301 trial, the baseline rTNSS score was the same across the olopatadine-mometasone group, the mometasone NS group, and the placebo group (mean = 10.1; SD = 1.2). In the GSP301-304 trial, the baseline mean rTNSS score was 10.1 (SD = 1.2) for the olopatadine-mometasone group, 10.3 (SD = 1.3) for the mometasone NS group, and 10.3 (SD = 1.2) for the placebo group. In the GSP301-305 trial, the baseline mean rTNSS score was 8.83 (SD = 1.41) for the olopatadine-mometasone group and 8.84 (SD = 1.66) for the placebo group.

Indirect evidence from 2 NMAs was submitted by the sponsor. One NMA evaluated the efficacy of olopatadine-mometasone compared with placebo, intranasal corticosteroids, and oral antihistamines among adolescent and adult patients (aged 12 years and older) with SAR. The other NMA assessed the efficacy of olopatadine-mometasone relative to placebo and intranasal corticosteroids in children (aged ≥ 6 to < 12 years) with SAR. The NMA for adolescent and adult patients was based on 13 RCTs identified from a sponsor-conducted SLR, while the NMA for children was based on 4 RCTs. Efficacy was measured using the 12-hour rTNSS in both NMAs.

The sponsor also submitted a long-term extension study that evaluated the long-term (52 weeks) safety, tolerability, and efficacy of olopatadine-mometasone in adults and adolescents (aged 12 years and older) with PAR. However, given that the Health Canada–approved indication is for SAR, not PAR, the long-term study submitted by the sponsor was not considered relevant to this review and was therefore not appraised.

Interpretation of Results

Efficacy

The patient group input highlighted that the key treatment goal for patients with SAR was to eliminate or significantly lessen AR symptoms, in particular, nasal symptoms. Relief of other symptoms and improvement of quality of life were also considered important goals of treatment by patients. Outcomes of the pivotal trials, GSP301-301, GSP301-304, and GSP301-305, were in line with the needs identified by patients, assessing nasal symptoms (12-hour rTNSS, 12-hour iTNSS), ocular symptoms (12-hour rTOSS), and HRQoL (RQLQ[S] as well as PRQLQ). In the included trials, baseline nasal and ocular symptom scores were lower for children (i.e., in the GSP301-305 trial) than those of adolescents and adults. For instance, the baseline 12-hour rTNSS score was 8.83 and 8.84 for the olopatadine-mometasone and placebo groups in the GSP301-305 trial, whereas the rTNSS score was greater than 10 across treatment groups in the adolescents and adults enrolled in the GSP301-301 and GSP301-304 trials. This is likely due to the difference in inclusion criteria, as the GSP301-305 trial required children to have a minimum rTNSS score of 6, while the GSP301-301 and GSP301-304 trials required a minimum score of 8; however, the actual reason for and overall impact of this difference in criteria remain unclear. According to the clinical experts consulted by the review team, lower baseline scores might also have contributed to the smaller treatment effect observed in the GSP301-305 trial and a possible underestimation of the treatment effect, because lower scores leave a smaller margin for effect sizes in children.

The GSP301-301 and GSP301-304 studies had similar study populations, interventions, comparators, outcomes, and study designs, and focused on the adolescent and adult patient populations (aged 12 years and older). Evidence from both trials demonstrated with high certainty that, compared with placebo, olopatadine-mometasone results in a statistically significant improvement in nasal symptoms as measured by the 12-hour rTNSS and 12-hour iTNSS. The LS mean difference in the 12-hour rTNSS was consistent between the GSP301-301 and GSP301-304 trials in terms of the direction and magnitude of the treatment effect, with LS mean differences of −0.98 points (95% CI, −1.38 to −0.57) in the GSP301-301 trial and −1.09 points (95% CI, −1.49 to −0.69) in the GSP301-304 trial. Using the threshold of a minimal important difference (MID) of 0.5 points, described by the clinical experts, the results also indicated a clinically meaningful improvement favouring olopatadine-mometasone over placebo. Evidence from the GSP301-301 and GSP301-304 trials also indicated that, compared with placebo, treatment with olopatadine-mometasone in adolescent and adult patients likely results in an improvement in ocular symptoms; however, there was uncertainty in the clinical meaningfulness of the results because the 95% CIs included the MID threshold, suggesting that the results were consistent with both a clinically meaningful benefit and no meaningful benefit for this outcome.

The GSP301-305 trial compared olopatadine-mometasone with placebo in children (aged ≥ 6 years and < 12 years) with SAR. Evidence from the GSP301-305 trial was generally in line with the evidence from the GSP301-301 and GSP301-304 trials, demonstrating that olopatadine-mometasone likely results in an improvement in nasal symptoms as measured by the 12-hour rTNSS (LS mean difference = −0.6 points; 95% CI, −0.9 to −0.2) and 12-hour iTNSS (LS mean difference = −0.6 points; 95% CI, −1.0 to −0.3), but likely results in little or no difference in improving ocular symptoms as measured by the rTOSS (LS mean difference = −0.2 points; 95% CI, −0.6 to 0.1). None of these outcomes were considered clinically meaningful because the 95% CIs included the MID of 0.5 points. The clinical experts consulted by the review team noted there was a possibility of underestimating the relative efficacy between olopatadine-mometasone and placebo in children because the caregivers assisting children may report symptom scores that inaccurately assess symptom severity.

When comparing olopatadine-mometasone with mometasone NS in the GSP301-301 and GSP301-304 trials, there was inconsistency in the statistical significance and clinical meaningfulness of the efficacy end points across trials. The results for nasal or ocular symptom outcomes (i.e., rTNSS, iTNSS, rTOSS) were statistically significantly in favour of olopatadine-mometasone in the GSP301-304 trial, but not in the GSP301-301 trial. The evidence from these trials indicated with low to moderate certainty that the difference in improving nasal or ocular symptoms, although favouring olopatadine-mometasone, was not clinically meaningful. Across trials, there was inconsistency in the results for rTNSS and rTOSS between the GSP301-301 and GSP301-304 trials; however, only the inconsistency in rTOSS was determined to be serious, based on the relative position of the point estimates and the extent to which the 95% CIs overlapped, which might have introduced further uncertainty in the certainty of evidence. The LS mean difference in the 12-hour rTOSS between olopatadine-mometasone and mometasone NS was −0.19 points (95% CI, −0.49 to 0.11) in the GSP301-301 trial, with the point estimate lying near the no-effect line (i.e., between-group difference = 0) and with the 95% CI crossing the no-effect line. The LS mean difference in the 12-hour rTOSS between olopatadine-mometasone and mometasone NS was −0.35 points (95% CI, −0.66 to −0.03) in the GSP301-304 trial, with the point estimate lying near the MID (i.e., a between-group difference of > 0.5 points) and with the 95% CI excluding the no-effect line.

HRQoL was investigated in all 3 pivotal trials using the RQLQ(S) in the adolescent and adult population, and the PRQLQ in the child population, both of which are validated measurement instruments in these populations. The MID for within-group change in the Rhinoconjunctivitis Quality-of-Life Questionnaire has been reported for both the adolescent and adult population.^52,53 However, there is no validated MID for between-group changes identified from the literature. A between-group difference of 0.5 was provided by the clinical experts as the MID for both the RQLQ(S) and PRQLQ. In general, the results of the RQLQ(S) in the adolescent and adult population between olopatadine-mometasone versus placebo and mometasone NS, as well as the results of the PRQLQ in the child population between olopatadine-mometasone versus placebo, favoured olopatadine-mometasone, based on the point estimate and 95% CI with moderate to high certainty. However, these results were not clinically meaningful (i.e., MID was crossed by the 95% CIs).

In the 3 pivotal trials, treatment with olopatadine-mometasone was administered for up to 17 days. According to the clinical experts consulted by the review team, patients in the real world are often given therapy for longer than the duration used in the trials. As such, the long-term efficacy of olopatadine-mometasone beyond 17 days remains unknown.

The sponsor-submitted ITCs included 1 NMA in adolescents and adults (aged 12 years and older) and 1 NMA in children (aged ≥ 6 to < 12 years) that evaluated the relative efficacy of olopatadine-mometasone compared with placebo and 2 drug classes, including intranasal corticosteroids and oral antihistamines. Echoing the evidence from the pivotal trials, olopatadine-mometasone was favoured over placebo in terms of improving the 12-hour rTNSS in the adolescent and adult population (mean or LS mean difference of −1.26 points; 95% CrI, −1.86 to −0.67) and in the child population (mean or LS mean difference of −1.21 points; 95% CrI, −1.86 to −0.56). In addition, the robustness of the results from the base-case analysis in the adolescent and adult population was supported by 2 sensitivity analyses that removed 2 trials with missing values for SEs or that included only 5 trials with LS mean change from baseline as an end point. In the base-case analyses of adolescents and adults, although the point estimates of mean or LS mean difference in the 12-hour rTNSS favoured olopatadine-mometasone over intranasal corticosteroids or oral antihistamines, the 95% CrIs of the mean or LS mean difference crossed the no-effect line (i.e., difference = 0), suggesting there was no difference between olopatadine-mometasone and these treatments. In the NMA for children with SAR, olopatadine-mometasone was favoured over the intranasal corticosteroids category (mean or LS mean difference of −0.94 points; 95% CrI, −1.63 to −0.26) in the 12-hour rTNSS. However, uncertainty existed in these NMA findings due to limitations of the NMAs, which is discussed in the critical appraisal section. For instance, relevant comparators were missing from the SLR protocol that might have resulted in bias due to missing evidence. Additionally, the fact that only loratadine was included in the oral antihistamine node in the adolescents and adults NMA, and only mometasone and ciclesonide were included in the intranasal corticosteroid node in the children NMA, raised concerns about whether only 1 or 2 individual therapies would properly represent the corresponding drug class in terms of efficacy.

The clinical experts also noted that Dymista antihistamine NS (i.e., azelastine hydrochloride) and corticosteroid NS (i.e., fluticasone propionate) were not included in the NMA conducted by the sponsor, yet were considered relevant comparators to olopatadine-mometasone. Dymista is approved by Health Canada for the symptomatic treatment of moderate to severe SAR and associated ocular symptoms in adults, adolescents, and children aged 6 years and older; however, it is not reimbursed by the public drug plans in Canada; thus, this remains a gap in the evidence.

Harms

In the GSP301-301, GSP301-304, and GSP301-305 trials, dysgeusia, which is a known side effect of olopatadine, was the most common TEAE across the olopatadine-mometasone groups, although frequencies in the 3 trials were low (3.3%, 3.7%, and 1.3%, respectively). Across all groups in the GSP301-301 trial, only 1 patient (0.3%) in the olopatadine-mometasone group had a TESAE, which was a spontaneous abortion. In the GSP301-304 trial, no patients in the olopatadine-mometasone group had TEAEs, while 1 patient in the mometasone NS group (0.3%) had 1 TESAE (i.e., peritonsillar abscess), and 1 patient in the placebo group (0.3%) had 3 TESAEs (including 1 instance each of osteomyelitis, syncope, and foot fracture). In the GSP301-305 trial, no patients in the olopatadine-mometasone group had a TEAE, and 1 patient (0.5%) in the placebo group had a TESAE. No patients in the olopatadine-mometasone group discontinued from the study due to TEAEs in either the GSP301-301 or GSP301-304 trials, while 4 patients (1.8%) in the olopatadine-mometasone group in the GSP301-305 trial withdrew due to TEAEs, including due to 1 instance each of conjunctivitis, acute otitis media, and sinusitis, and 1 instance of upper respiratory tract infection. No deaths were reported in any of the pivotal trials. Overall, the clinical experts consulted by the review team noted that olopatadine-mometasone was safe in adults, adolescents, and children with SAR, and the harms observed in patients treated with olopatadine-mometasone were expected and manageable.

Harms were not examined in the sponsor-submitted NMA; thus, there is a gap in the evidence with respect to the safety of olopatadine-mometasone relative to intranasal corticosteroids and oral antihistamines. However, this was not considered by the clinical experts consulted by the review team to be a critical gap, who stated there was no reason to suspect additional or new safety concerns with olopatadine-mometasone based on the safety data available for individual components and other intranasal corticosteroids with similar excipients.

Conclusion

The sponsor submitted 3 phase III, double-blind, RCTs: GSP301-301, GSP301-304, and GSP301-305. Both the GSP301-301 (N = 1,176) and GSP301-304 (N = 1,180) trials compared the efficacy of olopatadine-mometasone with placebo and the individual constituent monotherapies (i.e., olopatadine hydrochloride NS and mometasone NS) in adolescent and adult patients (aged 12 years and older) with SAR, while the GSP301-305 trial (N = 446) assessed the efficacy of olopatadine-mometasone relative to placebo in children (aged ≥ 6 to < 12 years) with SAR. Compared with placebo, the evidence from the 3 pivotal trials showed added clinical benefits of olopatadine-mometasone in reducing nasal and ocular symptoms. Results from the GSP301-301 and GSP301-304 trials suggested with moderate to high certainty that olopatadine-mometasone, compared with placebo, results in an improvement in the 12-hour rTNSS, 12-hour iTNSS, and 12-hour rTOSS in adolescent and adult patients with SAR. Evidence from the GSP301-305 trial also suggested improvements in rTNSS and iTNSS with olopatadine-mometasone compared with placebo with moderate certainty, but not for ocular symptoms. Compared with mometasone NS in adolescent and adult patients, although the results for nasal and ocular symptoms favoured olopatadine-mometasone, they were not clinically meaningful. Olopatadine-mometasone was considered safe in adolescents, adults, and children with SAR because the harms observed in patients treated with olopatadine-mometasone were expected and manageable, given the known safety profiles of the individual excipients.

The indirect evidence submitted by the sponsor included 1 NMA in adolescent and adult patients with SAR and 1 NMA in children with SAR. The results of the NMAs were consistent with the pivotal trial, favouring olopatadine-mometasone over placebo in both analysis populations. In the NMA in children, olopatadine-mometasone was favoured over intranasal corticosteroids, but there was no difference between these treatments in the adolescents and adults NMA. There was also no difference between olopatadine-mometasone and oral antihistamines in the adolescents and adults NMA. Overall, the findings from the 2 NMAs were uncertain due to limitations surrounding the comparators considered and whether there was appropriate representation in the comparator drug classes in terms of efficacy.

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63.Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMed

64.Fedorov S. GetData graph digitizer [sponsor-supplied reference]. 2020. https://getdata-graph-digitizer.com/index.php

65.Dias S, Welton NJ, Sutton AJ, Ades AE. A generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials (NICE Decision Support Unit Technical Support Documents) [sponsor-supplied reference]. National Institute for Health and Care Excellence (NICE); 2014. Accessed 2014. https://www.ncbi.nlm.nih.gov/books/NBK310366/

66.Gabry J, Simpson D, Vehtari A, Betancourt M, Gelman A. Visualization in bayesian workflow. Journal of the Royal Statistical Society Series A: Statistics in Society. 2019;182(2):389-402. doi:10.1111/rssa.12378

67.Anolik R, Mometasone Furoate Nasal Spray With Loratadine Study Group. Clinical benefits of combination treatment with mometasone furoate nasal spray and loratadine vs monotherapy with mometasone furoate in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100(3):264-71. doi:10.1016/S1081-1206(10)60452-8 PubMed

68.Actavis Inc. NCT01850823: Clinical Equivalence Study of Mometasone Nasal Spray [sponsor-supplied reference]. ClinicalTrials.gov; 2020. Accessed 2020. https://clinicaltrials.gov/ct2/show/NCT01850823

69.Teva Branded Pharmaceutical Products R&D, Inc. NCT01024608: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study to Assess the Efficacy and Safety of Beclomethasone Dipropionate Hydrofluoroalkane (BDP HFA) Nasal Aerosol in Subjects 12 Years of Age and Older With SAR [sponsor-supplied reference]. ClinicalTrials.gov; 2021. Accessed December 1, 2021. https://clinicaltrials.gov/study/NCT01024608

70.Organon and Co. NCT03882047: Efficacy and Safety of Mometasone Furoate Aqueous Nasal Spray vs Placebo and Flonase® (Fluticasone Propionate) in Seasonal Allergic Rhinitis Patients (I94-001) [sponsor-supplied reference]. ClinicalTrials.gov; 2022. Accessed February 7, 2022. https://clinicaltrials.gov/study/NCT03882047

71.Organon and Co. NCT03855189: Safety and Efficacy of SCH 32088 vs Beclomethasone Dipropionate (Vancenase AQ) and Placebo in Seasonal Allergic Rhinitis [sponsor-supplied reference]. ClinicalTrials.gov; 2022. Accessed February 7, 2022. https://clinicaltrials.gov/study/NCT03855189

72.Teva Pharmaceuticals USA. NCT02246920: A Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Multi-Site Study to Compare the Therapeutic Equivalence of Fluticasone Propionate Nasal Spray, 50 mcg With Flonase® Nasal Spray in the Relief of the Signs and Symptoms of Seasonal Allergic Rhinitis [sponsor-supplied reference]. ClinicalTrials.gov; 2023. Accessed May 11, 2023. https://clinicaltrials.gov/study/NCT02246920

73.Organon and Co. NCT00732381: Placebo-Controlled Study of Mometasone Furoate Nasal Spray (MFNS) 200 mcg QD in the Relief of Nasal Congestion Associated With Seasonal Allergic Rhinitis (SAR) [sponsor-supplied reference]. ClinicalTrials.gov; 2024. Accessed May 8, 2024. https://clinicaltrials.gov/study/NCT00732381

74.Gawchik S, Goldstein S, Prenner B, John A. Relief of cough and nasal symptoms associated with allergic rhinitis by mometasone furoate nasal spray. Ann Allergy Asthma Immunol. 2003;90(4):416-21. doi:10.1016/S1081-1206(10)61826-1 PubMed

75.Meltzer EO, Shekar T, Teper AA. Mometasone furoate nasal spray for moderate-to-severe nasal congestion in subjects with seasonal allergic rhinitis. Allergy Asthma Proc. 2011;32(2):159-67. doi:10.2500/aap.2011.32.3424 PubMed

76.Prenner BM, Lanier BQ, Bernstein DI, Shekar T, Teper A. Mometasone furoate nasal spray reduces the ocular symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol. 2010;125(6):1247-1253 e5. doi:10.1016/j.jaci.2010.03.004 PubMed

77.Ratner PH, Wingertzahn MA, van Bavel JH, Hampel F, Darken PF, Shah T. Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2006;118(5):1142-8. doi:10.1016/j.jaci.2006.07.050 PubMed

78.Berger WE, Nayak A, Lanier BQ, et al. Efficacy and safety of once-daily ciclesonide nasal spray in children with allergic rhinitis. Pediatr Asthma Allergy Immunol. 2008;21(2):73-82. doi:10.1089/pai.2007.0022.73

79.Sumitomo Pharma America, Inc. NCT01458275: A 2-Week Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Safety and Efficacy Study of Ciclesonide Nasal Aerosol in Subjects 6 to 11 Years With Seasonal Allergic Rhinitis [sponsor-supplied reference]. ClinicalTrials.gov; 2014. Accessed April 16, 2014. https://clinicaltrials.gov/study/NCT01458275

80.Organon and Co. NCT03879772: Dose-Ranging Study of Mometasone Furoate Nasal Spray (SCH 32088) in the Treatment of Children (Ages 6-11) With Seasonal Allergic Rhinitis [sponsor-supplied reference]. ClinicalTrials.gov; 2022. Accessed February 7, 2022. https://clinicaltrials.gov/study/NCT03879772

Pharmacoeconomic Review

Abbreviations

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Table 2: Summary of Economic Evaluation

AH = antihistamine; CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; INCS = intranasal corticosteroid; NMA = network meta-analysis; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; QALY = quality-adjusted life-year; SAR = seasonal allergic rhinitis.

^aIn the economic model, the sponsor considered INCSs to be represented by mometasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate. Costing for this group was based on the least costly generic drug (mometasone furoate). Efficacy for oral AHs from the sponsor’s NMA for children was represented by mometasone and ciclesonide, with the assumption that efficacy would be the same for all drugs in the class.

^bIn the economic model, the sponsor considered oral AHs to be represented by cetirizine, desloratadine, fexofenadine, and loratadine. Costing for this group was based on the least costly generic drug (cetirizine). Efficacy for oral AHs from the sponsor’s NMA was represented by loratadine, with the assumption that efficacy would be the same for all drugs in the class.

Conclusions

Based on the Canada’s Drug Agency (CDA-AMC) Clinical Review of the GSP301-301, GSP301-304, and GSP301-305 trials, the use of olopatadine hydrochloride and mometasone furoate nasal spray (olopatadine-mometasone) by adolescents and adults (aged 12 years and older) with moderate or severe seasonal allergic rhinitis (SAR) over a 14-day treatment course improves nasal and ocular symptoms, based on the 12-hour reflective Total Nasal Symptom Score (rTNSS) and reflective Total Ocular Symptom Score (rTOSS) outcomes compared with placebo. However, compared with mometasone furoate nasal spray, olopatadine-mometasone did not result in a clinically meaningful improvement in symptoms in this age group. Among children (aged 6 to 11 years), the trial evidence suggests that olopatadine-mometasone improves nasal symptoms compared with placebo over 14 days of treatment. In both age groups, olopatadine-mometasone had a nonstatistically significant impact on health-related quality of life (HRQoL) after 14 days of treatment.

There have been no head-to-head trials of olopatadine-mometasone versus oral antihistamines (AHs) or intranasal corticosteroids (INCSs) other than mometasone furoate nasal spray in the adolescent and adult subgroup. The indirect evidence submitted by the sponsor suggests there may be no meaningful difference in nasal symptoms between olopatadine-mometasone and oral AHs or INCSs in adults. Among children, the sponsor’s indirect evidence suggests that olopatadine-mometasone may improve nasal symptoms compared with INCSs; however, no evidence comparing olopatadine-mometasone with oral AHs was provided. The CDA-AMC Clinical Review noted that the findings from the sponsor’s network meta-analysis (NMA) should be viewed as uncertain, owing to the identified limitations. Ocular symptoms, HRQoL, and safety were not assessed in the sponsor’s NMA.

CDA-AMC was unable to address several key limitations with the sponsor’s economic submission, including uncertainty in the comparative clinical data, as well as methodological and conceptual limitations related to the model structure. These limitations prevented CDA-AMC from deriving a base-case estimate of the cost-effectiveness of olopatadine-mometasone for the treatment of moderate to severe SAR and associated ocular symptoms. The sponsor’s analysis suggests that the drug acquisition cost of olopatadine-mometasone will be offset by savings in health care costs; however, whether these predicted savings will be realized in clinical practice is highly uncertain, owing to the lack of clinical data to support reduced health care resource use with olopatadine-mometasone. Overall, there is insufficient clinical and economic evidence to suggest that olopatadine-mometasone should be priced higher than currently reimbursed treatments for moderate to severe SAR and associated ocular symptoms.

Input Relevant to the Economic Review

This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CDA-AMC review process.

Patient group input was provided by Asthma Canada and Allergy Quebec. Asthma Canada gathered feedback through its 2024 Annual Asthma Survey, which involved 1,407 patients and caregivers. Among these, 37% reported having allergic rhinitis (AR) as a comorbidity with asthma, and 63% had experienced SAR. They also conducted 2 one-on-one interviews with AR patients selected from survey respondents. Allergy Quebec did not perform any data collection from patients. Both organizations indicated that AR is associated with symptoms, including runny or itchy nose, nasal congestion, itchy or swollen eyes, headaches, sinus pressure, and fatigue, which can adversely affect daily life and quality of life. Respondents noted that the physical symptoms of AR are the most challenging aspect of their condition and emphasized the need for better treatments to reduce symptoms, including treatments that address rhinorrhea and do not trigger asthma flare-ups. Many respondents noted that their current treatments did not effectively control their allergic symptoms. Interviewed patients expressed concerns about treatment efficacy and side effects, including drowsiness and nasal dryness, and issues related to cost and accessibility, including insurance coverage and local pharmacy availability.

No clinician group input was received for this review.

The CDA-AMC participating drug plans sought clarification on the definition of the seasonal aspect of SAR, as some allergic triggers may be seasonal in some climates but perennial in others, with symptoms throughout most of the year. Additionally, the drug plans questioned whether diagnostic testing (e.g., skin prick or serum-specific immunoglobulin E test) is routinely done in clinical practice for SAR. The drug plans noted that the only other AH nasal spray in Canada (combination AH and corticosteroid product azelastine hydrochloride and fluticasone propionate [Dymista]) received a Do Not List recommendation from the Canadian Drug Expert Committee in 2015 and did not undergo negotiations with the pan-Canadian Pharmaceutical Alliance. Plans additionally noted the presence of confidential negotiated prices for comparators.

Several of these concerns were addressed in the sponsor’s model:

• Nasal symptoms associated with SAR were included in the sponsor’s model. Other symptoms noted to be important by patients (e.g., itchy and swollen eyes, headaches, fatigue) were not included in the model.

In addition, CDA-AMC addressed some of these concerns, as follows:

• CDA-AMC compared the acquisition costs of olopatadine-mometasone and relevant comparators.

CDA-AMC was unable to address the following concerns raised from the input:

• CDA-AMC was unable to assess the cost-effectiveness of olopatadine-mometasone for the treatment of SAR-associated ocular symptoms and, hence, for the full Health Canada indication.

• The CDA-AMC cost comparison is based on publicly available prices and does not consider the presence of confidential negotiated prices.

Economic Review

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

The sponsor submitted a cost-utility analysis comparing costs and outcomes for olopatadine-mometasone compared with oral AHs, INCSs, and placebo.¹ The sponsor assumed intraclass clinical equivalency between products from the same class. The modelled population was patients aged 6 years and older experiencing an episode of moderate to severe SAR, with separate analyses submitted for patients aged 6 to 11 years (hereafter referred to as children), and aged 12 years and older (hereafter referred to as adolescents and adults). The modelled population was aligned with the olopatadine-mometasone pivotal trials, which enrolled patients with a morning congestion score of at least 2 and an rTNSS score of at least 6 or 8 (≥ 6 in the GSP301-301 and GSP301-304 trials and ≥ 8 in the GSP301-305 trial). The modelled population is aligned with the Health Canada indication for olopatadine-mometasone.

Olopatadine-mometasone is available as a nasal spray containing a fixed dose of 665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate in each spray (bottle of 240 metered sprays). The recommended dosage of olopatadine-mometasone is 2 sprays in each nostril twice daily for adolescents and adults and 1 spray in each nostril twice daily for children.² At the submitted price of $56.11 per bottle, the daily per-patient cost of olopatadine-mometasone was estimated by the sponsor to be $0.94 for children and $1.87 for adolescents and adults.

The sponsor’s model predicts clinical outcomes in terms of quality-adjusted life-days, which the sponsor converted to quality-adjusted life-years (QALYs). The economic evaluation was conducted over a 28-day time horizon from the perspective of a Canadian public health care payer. No discounting was applied.

Model Structure

The sponsor’s submitted model was a decision tree with 3 health states: SAR, recovered from SAR, and extended SAR (Figure 1). All patients entered the model in the SAR health state and received olopatadine-mometasone, INCSs, or oral AHs (in adolescents and adults only). Patients who had a response to treatment within the first 2 weeks were assumed to have moved to the recovered from SAR state and to maintain that response for the remainder of the 28-day horizon. Patients who did not have a treatment response by day 14 were assumed to have moved to the extended SAR health state and to receive an additional 14 days of treatment. By day 28, all patients were expected to have responded. The sponsor assumed that no patients would be at risk of death due to SAR.

Model Inputs

Model populations were obtained from the GSP301-301 and GSP301-304 trials for the adolescent and adult subgroup (patients aged 12 years and older with a documented clinical history of SAR) and the GSP301-305 trial for the children subgroup (patients aged 6 to 11 years with a clinical history of SAR, diagnosed with a positive skin prick test within 12 months before screening). In the GSP301-301 and GSP301-304 trials, the mean age of patients was 39.3 and 39.6 years, respectively, and approximately 63% to 65% were female. In GSP301-305, the mean age of the study population was 8.7 years, and 56% of the patients in the olopatadine-mometasone group were male. Clinical efficacy inputs estimated treatment by the sponsor as follows: first, the sponsor used the pivotal trial data to determine the proportion of patients who had a 50% or greater reduction in rTNSS for olopatadine-mometasone and INCS comparators.³ Second, the sponsor used the results from the submitted NMA to estimate the relative risk (using the change from baseline for the 12-hour rTNSS) of responding to the therapies included in the model for both subgroups. Because the sponsor identified no relevant data for oral AHs in the children subgroup, the model did not include oral AHs for this subgroup.⁴

Adverse events (AEs) were reported by at least 1% of patients, based on pooled estimates from the GSP301-301 and GSP301-304 trials for olopatadine-mometasone and INCSs. The model considered only AEs that were reported in more than 1% of patients and AEs with a high impact on costs and outcomes. AEs for oral AHs were obtained from Kuna et al. (2009), based on a threshold of at least 1%.⁵

Health state utility values were obtained from the literature. The utility for the SAR health state was obtained from Retzler (2018).⁶ The health state utility value for the recovered from SAR state was obtained from Pollock (2023) and Ara (2011).^7,8 The sponsor estimated the utility value for the extended SAR state by taking the average of the utility values for the SAR and the recovered from SAR states.

The costs in the model included those related to drug acquisition, resource use, diagnostic testing, and AEs. Drug acquisition costs were calculated by the sponsor using the submitted price for olopatadine-mometasone and IQVIA DeltaPA database prices for comparators.⁹ The sponsor assumed that adolescents and adults would receive 2 sprays of olopatadine-mometasone in each nostril twice daily and that children would receive 1 spray in each nostril twice daily, as per the olopatadine-mometasone product monograph. Resource use costs included those associated with visits to general physicians, specialists, and the emergency department for SAR, as well as costs related to inpatient stays for SAR. Diagnostic testing costs included skin prick tests, allergen testing, chest radiographs, and electrocardiograms. Costs for resource use and diagnostic testing were obtained from the Ontario Schedule of Benefits and the literature.^10,11 Costs for the management of AEs were obtained from the Ontario Case Costing Initiative (2018).¹²

Summary of Sponsor’s Economic Evaluation Results

All analyses were run probabilistically (1,000 iterations), and the probabilistic results were similar to the deterministic results. The probabilistic findings are presented subsequently. The submitted analyses were based on the publicly available pricing for olopatadine hydrochloride and mometasone furoate monohydrate and other comparators. Additional results from the sponsor’s submitted economic evaluation base case are presented in Appendix 3.

Base-Case Results

Among adolescents and adults, olopatadine-mometasone was associated with a total treatment cost of $274 over the 28-day horizon. Of this, 11% ($29) was associated with drug acquisition and 89% ($245) was associated with health care resource use. Olopatadine-mometasone was predicted by the sponsor to be less costly (incremental savings = $20 to $27) compared with INCSs and AHs, owing to reduced health care resource use (reduced health care costs = $45 to $46), despite increased drug acquisition costs (increased acquisition costs = $20 to $25). The sponsor’s model additionally predicted that olopatadine-mometasone would be more effective (incremental gain in QALYs = 0.00031 to 0.00032) compared with INCSs and oral AHs. At a willingness-to-pay threshold of $50,000 per QALY gained, the probability of olopatadine-mometasone being cost-effective was 62%.

Table 3: Summary of the Sponsor’s Economic Evaluation Results (Adolescents and Adults)

ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.

Note: Placebo was included as a comparator in the sponsor’s submission to align with trial data. Results that align with trial data are presented in Appendix 3.

Source: Sponsor’s pharmacoeconomic submission.¹

Among children, olopatadine-mometasone was associated with a total treatment cost of $244 over the 28-day time horizon. Of this, 6% ($14) was associated with drug acquisition and 93% ($228) was associated with health care resource use. Olopatadine-mometasone was predicted by the sponsor to be less costly (incremental savings = $47) compared with INCSs, owing to reduced health care resource use (reduced health care costs = $59), despite increased drug acquisition costs (increased acquisition costs = $12). The sponsor’s model additionally predicted that olopatadine-mometasone will be more effective (incremental gain in QALYs: 0.0004) compared with INCSs.

Table 4: Summary of the Sponsor’s Economic Evaluation Results (Children)

ICER = incremental cost-effectiveness ratio; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray; QALY = quality-adjusted life-year.

Note: Oral antihistamines were not included as comparators in the subgroup of children aged 6 to 11 years.

Source: Sponsor’s pharmacoeconomic submission.¹

Sensitivity and Scenario Analysis Results

The sponsor provided deterministic scenario analyses exploring the impact of modelling response rates using NMA results and adopting alternative sources to assign utility weights to health states. The scenario analyses with the greatest impact on the incremental cost-effectiveness ratio (ICER) were changes to the source of efficacy. In the adolescents and adults subgroup, when the source of efficacy was derived from the NMA results, olopatadine-mometasone was more costly than INCSs, resulting in an ICER of $80,807 per QALY gained. Alternatively, in the children subgroup, this scenario analysis resulted in outputs similar to the sponsor’s base-case analysis (i.e., olopatadine-mometasone dominated all other comparators).

The sponsor additionally conducted a scenario analysis from a societal perspective that included costs related to absenteeism and presenteeism for adults and costs of informal caregiving for children. The results of this analysis were similar to the sponsor’s base case for both subgroups.

CDA-AMC Appraisal of the Sponsor’s Economic Evaluation

CDA-AMC identified several key limitations to the sponsor’s analysis that have notable implications on the economic analysis:

• The comparative efficacy and safety of olopatadine-mometasone is highly uncertain. In the economic evaluation, olopatadine-mometasone was compared with INCSs and oral AHs, with efficacy informed by the sponsor-submitted NMAs. There have been no head-to-head trials of olopatadine-mometasone comparing it with any INCSs or oral AHs, and the CDA-AMC Clinical Review identified notable limitations with the sponsor’s NMAs. Notably, some nodes in the NMA were represented by 1 or 2 drugs. For example, in the adolescents and adults NMA, the efficacy of oral AHs was represented entirely by loratadine (i.e., it was the only treatment included within the oral AH node). However, in the sponsor-submitted model, the cost and recommended dosage of cetirizine were used to determine the treatment costs of oral AHs. Although the sponsor assumed that all drugs within a class are equally effective, the clinical experts consulted by CDA-AMC noted that some relevant comparators were not included in the sponsor’s systematic literature review (SLR) protocol. For example, fluticasone furoate, bilastine, and rupatadine fumarate are indicated and prescribed for the treatment of moderate to severe SAR. As noted in the CDA-AMC Clinical Review, the sponsor’s SLR report did not provide any rationale for why these treatments were not included. The omission of relevant comparators from the sponsor’s SLR protocol may have led to missing evidence in the subsequent NMAs. The impact of this potential bias on the results of the NMA and, hence, the economic evaluation, remains unknown. Overall, the NMA was considered too uncertain by the CDA-AMC Clinical Review team to support decision-making.

  In the economic model, the sponsor included AEs that occurred in at least 1% of the patients in their respective pivotal trials. These included dysgeusia, epistaxis, nasal discomfort, headaches, and drowsiness. Data to inform the rate of these AEs were incorporated in the model through a naive comparison, without adjustment or accounting for differences in patient characteristics. Owing to the direct use of clinical trial data, it is not possible to determine whether any observed differences between the therapies are solely due to the treatment or, rather, due to bias or confounding factors.

  • The sponsor’s model predicts that olopatadine-mometasone will be associated with an incremental gain of approximately 0.0003 QALYs over the 28-day model horizon compared with oral AHs and INCSs in the adolescents and adults subgroup, and with an incremental gain of approximately 0.0004 QALYs compared with INCSs in the children subgroup. Given the lack of direct evidence for olopatadine-mometasone versus relevant comparators, limitations with the sponsor’s indirect treatment comparison, and the use of a naive comparison for AEs, it is highly uncertain whether olopatadine-mometasone provides a net clinical benefit relative to currently available treatments.

• Health care resource use is highly uncertain. The sponsor’s model included health care resource use for patients with moderate to severe SAR (i.e., emergency department visits, physician visits, specialist visits, inpatients costs), both in the first 14 days of treatment as well as in the second 14 days among patients without an initial treatment response (i.e., extended SAR period). CDA-AMC notes that the cost savings predicted by the sponsor’s model with olopatadine-mometasone are driven by savings in health care resource use, particularly in the extended SAR period. Health care resource use was not an outcome in any of the included trials (GSP301-301, GSP301-304, GSP301-305), and resource use in the sponsor’s model (proportion of patients who require each resource, number of resources used by each patient) was based on clinical expert input obtained by the sponsor. The clinical expert input received by CDA-AMC indicated that some resource use estimates in the model may be overestimated, in particular, the proportion of patients who visit an emergency department (15%) or who are admitted to hospital (5%) in the extended SAR period.

  • CDA-AMC was unable to address this limitation. In the absence of robust studies of health care resource use for patients with SAR in Canada, health care resource use and, hence, the savings predicted by the sponsor’s model should be considered highly uncertain.

• SAR-associated ocular symptoms were not considered in the sponsor’s model. The indication for olopatadine-mometasone is for symptomatic treatment of moderate to severe SAR and associated ocular symptoms; however, the sponsor’s model included health states related only to treatment response in terms of nasal symptoms. As such, the sponsor’s model does not consider efficacy or costs related to ocular symptoms. The clinical expert input received by CDA-AMC for this review indicated that ocular symptoms are common among patients with SAR and can result in additional resource use. Data from the olopatadine-mometasone pivotal trials suggest that olopatadine-mometasone likely improves ocular symptoms (assessed via rTOSS) compared with placebo in adolescents and adults, with little to no difference among children. Ocular symptoms were not included in either the sponsor’s NMA or the comparative efficacy; hence, the cost-effectiveness of olopatadine-mometasone for the treatment of SAR-associated ocular symptoms is unknown.

  • CDA-AMC was unable to address this limitation. The omission of SAR-associated ocular symptoms from the economic model increases uncertainty as to the incremental benefits and costs associated with the use of olopatadine-mometasone for the full Health Canada indication.

• Oral AHs were not included as comparators in the child subgroup. The sponsor justified the exclusion of oral AHs in this subgroup by stating that no relevant data were identified for oral AHs in the child population. However, as noted in an earlier appraisal point, the sponsor’s SLR protocol omitted some relevant oral AHs (i.e., bilastine and rupatadine). As such, CDA-AMC is unable to comment on the validity of this statement. The clinical expert input received by CDA-AMC indicated that oral AHs are prescribed to children with moderate to severe SAR; as such, the omission of oral AHs does not represent Canadian clinical practice.

  • CDA-AMC was unable to address this limitation. The cost-effectiveness of olopatadine-mometasone relative to oral AHs in children is unknown.

• The impact of olopatadine-mometasone on HRQoL is uncertain. The impact of olopatadine-mometasone on HRQoL and, hence QALYs, predicted by the sponsor’s model, is uncertain for several reasons. First, as noted in the CDA-AMC Clinical Review, olopatadine-mometasone likely results in little to no difference in either HRQoL after 15 days of treatment compared with either placebo or mometasone alone in adolescents and adults or compared with placebo in children. No data were provided beyond 15 days; as such, the HRQoL impact of olopatadine-mometasone in the extended SAR phase (days 14 to 28) is unknown.

  Second, there is considerable uncertainty associated with the health state utility values adopted by the sponsor, as a result of using utility values from multiple sources and averaging utility values. For example, for the SAR health state, which reflects patients with either moderate or severe SAR, the sponsor averaged the reported utilities for moderate SAR (0.86 for the adult subgroup and 0.68 for the child subgroup) and severe SAR (0.83 for the adult subgroup and 0.65 for the child subgroup) to inform the model health states. Although the exact utility for this health state is uncertain, the utility value lacks face validity (i.e., does not reflect the utility of either moderate or severe SAR), as the clinical experts consulted by CDA-AMC indicated that patients with moderate SAR generally have different HRQoL compared with patients with severe SAR. The use of an average weight additionally makes the implicit assumption that there is an equal distribution of patients with moderate and severe SAR, which is uncertain. Additionally, to inform the utility weights for the extended SAR health state (patients whose condition does not respond to treatment in the first 14 days and receive an additional 14 days of treatment), the sponsor took the average of utilities for the SAR health state (0.87) and the recovered SAR health state (0.92), which results in a utility of 0.88 for patients whose condition does not respond to initial treatment. Although the exact utility for this health state is uncertain, the clinical experts consulted by CDA-AMC indicated that a higher utility for those whose condition does not respond to initial treatment lacks face validity and indicated that patient HRQoL in the second 14 days of treatment (extended SAR health state) would likely be the same or worse compared with the first 14 days of treatment (SAR health state).

  • The sponsor’s model predicts that olopatadine-mometasone will be associated with an incremental gain of approximately 0.0003 QALYs over a 28-day period. Whether this marginal gain will be realized in practice is highly uncertain owing to uncertainty in the underlying clinical evidence.

• Adherence to treatment was not considered. The sponsor’s model does not consider adherence to olopatadine-mometasone or comparators, thus implicitly making the assumption that patients will be fully adherent to treatment. The clinical expert input received by CDA-AMC indicated that patients may not fully adhere to treatment in practice, for example, if they perceive no or insufficient improvement after using the treatment a few times. In the olopatadine-mometasone pivotal trials, an adherence rate of between 75% and 125% (i.e., twice a day for 14 days = 100%; twice a day for up to 17 days = 125%) was achieved by more than 90% of patients in each treatment group. If adherence is lower in clinical practice, efficacy may be lower than estimated with no impact on costs.

  • CDA-AMC was unable to explore uncertainty in the impact of adherence on the cost-effectiveness of olopatadine-mometasone due to the structure of the sponsor’s model. The directionality of impact on the cost-effectiveness of olopatadine-mometasone is unknown because of a lack of adherence data for comparators.

Additionally, the following key assumptions were made by the sponsor and have been appraised by CDA-AMC (Table 5).

Table 5: Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission)

CDA-AMC = Canada’s Drug Agency; IgE = immunoglobulin E.

CDA-AMC Reanalyses of the Economic Evaluation

Base-Case Results

CDA-AMC was unable to address several key limitations with the sponsor’s submission, including uncertainty in the comparative clinical data as well as methodological and conceptual limitations related to the model structure. These limitations prevented CDA-AMC from deriving a base-case estimate of the cost-effectiveness of olopatadine-mometasone for the treatment of moderate to severe SAR and associated ocular symptoms.

As noted in the CDA-AMC Clinical Review, the findings of the NMA should be viewed with uncertainty; that is, it is unclear whether olopatadine-mometasone will result in improved outcomes compared with INCSs or AHs in either subgroup. Thus, CDA-AMC undertook a comparison of drug acquisition costs for olopatadine-mometasone and relevant comparators (Table 6 and Table 7). Readers should note that this analysis assumes equal efficacy between olopatadine-mometasone, which is uncertain, owing to the limitations identified with the submitted indirect evidence (refer to CDA-AMC Clinical Review).

In the CDA-AMC cost comparison, the drug acquisition cost of olopatadine-mometasone for a 14-day treatment course was $26 for adolescents and adults and $13 for children, based on the Health Canada–recommended dosage. It should be noted, however, that olopatadine-mometasone is available in Canada only as a 240-spray bottle at a submitted price of $56.11 per bottle. Thus, the acquisition cost for olopatadine-mometasone for a first course of treatment would be $56.11.

The cost of oral AHs for a 14-day treatment course ranged from $3 to $17 for adolescents and adults and from $3 to $11 for children, while a 14-day treatment course of INCSs ranged from $4 to $15 in adolescents and adults and from $2 to $7 for children (note that costs may be higher cost owing to per-bottle costs for INCSs; refer to Appendix 1). The price reductions required for the treatment cost of olopatadine-mometasone for a 14-day treatment course to be equivalent to that of the lowest-cost comparators in both the adult and children subgroups are shown in Table 6 and Table 7.

Table 6: Summary of the CDA-AMC Cost Comparison Analysis (Adolescents and Adults)

CDA-AMC = Canada’s Drug Agency; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray.

Note: The cost of olopatadine-mometasone per 14-day treatment course is estimated to be $26 for adolescents and adults (≥ 12 years) based on the sponsor’s submitted price ($56.11 per bottle of 240 metered sprays). At the monograph-recommended dosages, each 240-spray bottle contains sufficient product for 30 days for adolescents and adults (must be used within 2 months of opening). The CDA-AMC reanalysis is based on publicly available prices of the comparator treatments.

Table 7: Summary of the CDA-AMC Cost Comparison Analysis (Children)

CDA-AMC = Canada’s Drug Agency; NA = not applicable; olopatadine-mometasone = olopatadine hydrochloride and mometasone furoate nasal spray.

Note: Cost of olopatadine-mometasone per 14-day treatment course is estimated to be $13 for children (6 to 11 years) based on the sponsor’s submitted price ($56.11 per 240 metered spray bottle). At the monograph-recommended dosages, each 240-spray bottle contains sufficient product for 60 days for children (must be used within 2 months of opening). The CDA-AMC reanalysis is based on publicly available prices of the comparator treatments. NA indicates that the treatment was excluded as a comparator in the subgroup of children aged 6 to 11 years.

Issues for Consideration

• Each bottle of olopatadine-mometasone contains 240 metered sprays, which reflects 1 month of dosing for adults or 2 months of dosing for children. Although the duration of treatment for 1 episode of SAR may be approximately 14 days (based on the duration of the olopatadine-mometasone pivotal trials and the clinical expert input received by CDA-AMC), the full cost of 1 bottle would be incurred by payers (submitted price = $56.11). The olopatadine-mometasone monograph indicates that a bottle must be used within 2 months of first opening.

• The sponsor’s cost-utility analysis and the CDA-AMC cost comparison rely on publicly accessible list prices and do not reflect the existing confidential prices negotiated by public plans. It is likely that the prices paid by public drug plans are lower than the values used in each analysis.

• The olopatadine-mometasone pivotal trials included only patients with SAR. The clinical experts consulted by CDA-AMC noted that the results of these trials may be potentially generalizable to other types of AR, including perennial AR, and that off-label use may occur in practice.

Overall Conclusions

Based on the CDA-AMC Clinical Review of the GSP301-301, GSP301-304, and GSP301-305 trials, use of olopatadine-mometasone by adolescents and adults (aged 12 years and older) with moderate or severe SAR over a 14-day treatment course improves nasal and ocular symptoms (based on 12-hour rTNSS and rTOSS outcomes) compared with placebo. However, compared with mometasone furoate nasal spray, olopatadine-mometasone did not result in a clinically meaningful improvement in symptoms in this age group. Among children (aged 6 to 11 years), trial evidence suggests that olopatadine-mometasone improves nasal symptoms compared with placebo over 14 days of treatment. In both age groups, olopatadine-mometasone had a nonstatistically significant impact on HRQoL after 14 days of treatment.

There have been no head-to-head trials comparing olopatadine-mometasone with oral AHs or INCSs (other than mometasone furoate nasal spray), and the submitted indirect evidence was deemed by the CDA-AMC review team to be uncertain due to limitations surrounding the comparators considered and whether there was appropriate representation in the comparator drug classes in terms of efficacy, and a possibility of overestimation of the treatment effect estimates in some analyses. CDA-AMC identified additional important limitations with the sponsor’s economic evaluation that precluded reanalysis, including (but not limited to) uncertainty related to SAR-related health care resource use, the lack of consideration of SAR-related ocular symptoms, and the exclusion of oral AHs from the child subgroup. Due to limitations with the available comparative evidence and the sponsor’s economic evaluation, CDA-AMC was unable to provide a more robust estimate of the cost-effectiveness of olopatadine-mometasone compared with relevant comparators.

The sponsor’s model predicts that olopatadine-mometasone will be associated with a marginal incremental gain of QALYs (approximately 0.0003 to 0.0004), and that the increased drug acquisition costs of olopatadine-mometasone will be offset by cost savings from a reduction in health care resource use. Whether olopatadine-mometasone will reduce health care costs among patients with moderate to severe SAR is highly uncertain, given that health care resource use was not an outcome in the olopatadine-mometasone pivotal trials. Further, this reduction in health care usage is predicated on differences in treatment response between olopatadine-mometasone and comparators; however, as noted previously, the findings of the sponsor’s NMA should be considered highly uncertain, and it is unclear whether there will be differences in treatment outcomes in clinical practice. If the efficacy of olopatadine-mometasone is not different from that of comparators, the predicted savings in health care costs will not be realized, and the reimbursement of olopatadine-mometasone will result in additional costs to the health care system.

Overall, the clinical and economic evidence submitted by the sponsor is insufficient to suggest that olopatadine-mometasone should be priced higher than currently reimbursed treatments for moderate to severe SAR and associated ocular symptoms.

References

1.Bausch Health, Canada Inc. Pharmacoeconomic evaluation [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Ryaltris (olopatadine hydrochloride and mometasone furoate), suspension, 665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate (as monohydrate) per delivered dose; nasal spray. June 21, 2024.

2.Glenmark Pharmaceuticals Canada Inc. Ryaltris (olopatadine hydrochloride and mometasone furoate): suspension, 665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate (as monohydrate) per delivered dose; nasal spray [product monograph]. September 21, 2022.

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