Drugs, Health Technologies, Health Systems
Indication: For the symptomatic treatment of moderate to severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.
Sponsor: Bausch Health, Canada Inc.
Final recommendation: Do not reimburse
Summary
What Is the Reimbursement Recommendation for Ryaltris?
Canada’s Drug Agency (CDA-AMC) recommends that Ryaltris should not be reimbursed by public drug plans for the symptomatic treatment of moderate-to-severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.
Why Did CDA-AMC Make This Recommendation?
Evidence from 3 clinical trials (2 in adolescent and adult patients with seasonal allergic rhinitis and 1 in children with seasonal allergic rhinitis) demonstrated that Ryaltris improved nasal and eye symptoms in people with seasonal allergic rhinitis compared to placebo. However, compared to mometasone nasal spray, the improvements were not clinically meaningful in adolescents and adults, and there was no comparative evidence available in children.
The indirect evidence evaluated the comparative efficacy of Ryaltris versus intranasal corticosteroids and oral antihistamines in adolescent and adult patients, and versus intranasal corticosteroids in children. There were limitations in the indirect evidence that precluded meaningful conclusions on the efficacy of Ryaltris relative to active comparators in adolescent and adult patients or in children with seasonal allergic rhinitis.
Patients identified a need for new treatments that control the symptoms of seasonal allergic rhinitis and improve their quality of life. However, based on the evidence reviewed during the initial meeting and the reconsideration meeting, the Canadian Drug Expert Committee (CDEC) could not determine whether Ryaltris would address the unmet needs of patients because of the uncertainty around the benefit of Ryaltris versus appropriate active comparators.
Additional Information
What Is Seasonal Allergic Rhinitis?
Seasonal allergic rhinitis, also known as seasonal allergies, is typically induced by allergens such as pollen and leads to symptoms in the nose (e.g., nasal congestion, itching, runny nose, or sneezing) and eyes (e.g., itchiness, redness, or irritation). In Canada, approximately 3.5 million patients are affected by moderate-to-severe seasonal allergic rhinitis.
Unmet Needs in Seasonal Allergic Rhinitis
Not all patients respond to current treatments, and some treatments stop working over time. There is a need for additional therapies that relieve the symptoms of seasonal allergic rhinitis while reducing unpleasant side effects and substantially improve quality of life.
How Much Does Ryaltris Cost?
For each 14-day treatment period, Ryaltris is expected to cost approximately $13 per patient aged 6 to 11 years and $26 per patient aged 12 years and older.
CDEC recommends that olopatadine hydrochloride and mometasone furoate (olopatadine-mometasone) nasal spray not be reimbursed for the symptomatic treatment of moderate-to-severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older.
Although patients and clinicians identified the need for additional effective treatment options that control the symptoms of seasonal allergic rhinitis, improve health-related quality of life (HRQoL), and offer better treatment tolerance and adherence, CDEC could not conclude that olopatadine-mometasone nasal spray would adequately meet the unmet needs identified based on the submitted evidence.
Two phase III, double-blind, randomized controlled trials (RCTs) (GSP301-301 and GSP301-304) evaluating the efficacy and safety of olopatadine-mometasone nasal spray versus placebo and individual constituent monotherapies (i.e., olopatadine hydrochloride nasal spray and mometasone nasal spray) in adolescent and adult patients (aged 12 years and older) with moderate-to-severe seasonal allergic rhinitis, demonstrated that, although there was a benefit compared to placebo, when compared to mometasone nasal spray, olopatadine-mometasone resulted in inconsistent statistically significant results for improvement in nasal symptoms (as measured by 12-hour reflective Total Nasal Symptom Score [rTNSS] and instantaneous Total Nasal Symptom Score [iTNSS]) and ocular symptoms (as measured by 12-hour reflective Total Ocular Scale Score [rTOSS]). Additionally, the between-group differences for the results that did achieve statistical significance, were not clinically meaningful. Another phase III, double-blind RCT (GSP301-305) evaluating the efficacy and safety of olopatadine-mometasone nasal spray versus placebo in children (aged ≥ 6 to < 12 years) with moderate-to-severe seasonal allergic rhinitis, demonstrated that compared to placebo, olopatadine-mometasone resulted in statistically significant improvement in nasal symptoms, but not ocular symptoms. The between-group differences for the results that did achieve statistical significance were also not considered clinically meaningful. CDEC noted that there was moderate-to-high certainty that there was little-to-no difference between olopatadine-mometasone and comparators in all trials with respect to HRQoL, which was an outcome important to patients.
Though direct comparative evidence was available between olopatadine-mometasone and mometasone nasal spray from the GSP301-301 and GSP301-304 trials, there is a lack of direct comparative evidence for olopatadine-mometasone compared to other treatments for seasonal allergic rhinitis. As such, comparative evidence available for this review was based on 2 sponsor-submitted network meta-analyses (NMAs) which evaluated the comparative efficacy of olopatadine-mometasone versus intranasal corticosteroids, and oral antihistamines in adolescent and adult patients (aged 12 years and older), and versus intranasal corticosteroids in children (aged ≥ 6 to < 12 years). Overall, the NMAs were subject to important limitations and there was generally insufficient evidence to suggest that olopatadine-mometasone was better or worse than other established treatment options for seasonal allergic rhinitis, with most estimates affected by serious imprecision. Thus, CDEC could not draw conclusions on the comparative efficacy of olopatadine-mometasone.
Reconsideration request: The sponsor requested a reconsideration of the initial draft recommendation to not reimburse olopatadine-mometasone for the symptomatic treatment of moderate-to-severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older. There were 5 issues outlined by the sponsor in the request for reconsideration that were discussed by CDEC including considering the information from the Canadian Practice Parameter that intranasal antihistamines or intranasal corticosteroid combinations address the unmet needs of patients, revising CDEC claims that there is no evidence that olopatadine-mometasone improves adherence, revising CDEC statements about the appropriateness of the pivotal trial duration, removing statements that there were missing comparators, and removing claims that there were higher rates of dysgeusia with olopatadine-mometasone.
Unmet needs: During the initial meeting and the reconsideration meeting, CDEC discussed multiple unmet needs identified by patients and clinicians particularly that not all patients respond to current treatments, and some patients become refractory to available treatment options. Additionally, the need for additional therapies that modify the underlying disease mechanism of seasonal allergic rhinitis, as well as treatments that alleviate the symptoms of seasonal allergic rhinitis while reducing unpleasant side effects (e.g., drowsiness, stuffiness, or dry nose) and substantially improve HRQoL were considered. CDEC noted that compared to placebo, olopatadine-mometasone nasal spray may meet some of these needs as it results in clinically meaningful improvement in nasal symptoms (measured by 12-hour rTNSS) and in ocular symptoms (measured by 12-hour rTOSS). However, CDEC was unable to ascertain whether olopatadine-mometasone nasal spray meets the unmet needs identified versus currently available active treatments. No clinically meaningful improvement in nasal symptoms, ocular symptoms, or HRQoL were observed between olopatadine-mometasone nasal spray versus mometasone nasal spray in adolescents and adults with seasonal allergic rhinitis, and there was no direct comparative evidence available in children with seasonal allergic rhinitis. Although there are no serious concerns with the safety profile, olopatadine-mometasone nasal spray likely results in little-to-no difference in the occurrence of treatment emergent adverse events (TEAEs), compared to mometasone nasal spray; harms or HRQoL were not evaluated in the sponsor-submitted indirect evidence. Additionally, patients and clinicians highlighted a need for more convenient formulations that can also improve adherence. During both the initial and reconsideration meetings, CDEC discussed the potential for improved adherence with olopatadine-mometasone given the intranasal antihistamine and intranasal corticosteroid combination, and despite the high adherence rates observed in the GSP301-301 and GSP301-304 studies, CDEC emphasized that there was no evidence that olopatadine-mometasone improves adherence relative to other treatments for seasonal allergic rhinitis. Overall, CDEC was unable to conclude that olopatadine-mometasone nasal spray addressed the unmet needs identified within this review.
Certainty of evidence (GRADE): CDEC discussed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty of evidence assessment of the clinical trials. CDEC noted that compared to placebo, olopatadine-mometasone generally resulted in an improvement in nasal and ocular symptoms with moderate-to-high certainty. However, the GRADE assessment concluded that there is little-to-no difference when comparing olopatadine-mometasone nasal spray to mometasone nasal spray for nasal symptoms (moderate certainty), ocular symptoms (low certainty), HRQoL (high certainty), or treatment emergent serious adverse events (TESAEs) (moderate certainty). Furthermore, CDEC discussed the inconsistency in the statistical significance of the results for comparisons of olopatadine-mometasone and mometasone nasal spray, citing that the results were often not clinically meaningful. During the reconsideration meeting, CDEC acknowledged the focused allergic rhinitis practice parameter for Canada that was submitted by the sponsor as part of the reconsideration request. However, CDEC found it nonspecific regarding individual treatments and therefore considered it inconclusive and uncertain.
Indirect evidence: During the initial meeting and the reconsideration meeting, CDEC discussed the indirect evidence, as well as the relevant comparators for this review. CDEC noted that only 1 active comparator available in Canada (i.e., mometasone furoate nasal spray) was assessed in the clinical trial evidence for adolescents and adults (GSP301-301 and GSP301-304; olopatadine hydrochloride nasal spray was evaluated in GSP301-301 and GSP301-304 but is not available in Canada; thus, was not included in the CDA-AMC clinical report), and there are other effective treatment options available for patients with seasonal allergic rhinitis. CDEC discussed the sponsor-submitted NMAs comparing olopatadine-mometasone nasal spray with placebo, intranasal corticosteroids, and oral antihistamines in adolescent and adult patients (aged 12 years and older) with seasonal allergic rhinitis and compared to placebo and intranasal corticosteroids in children (aged ≥ 6 to < 12 years) with seasonal allergic rhinitis. In the NMA in children, olopatadine-mometasone was favoured over intranasal corticosteroids (−0.94 points [95% credible interval [CrI], −1.63 to −0.26 points]), but there was no difference between these treatments in the adolescent and adult NMA. There was also no difference between olopatadine-mometasone and oral antihistamines in the adolescent and adult NMA. During the initial meeting and the reconsideration meeting, CDEC emphasized the limitations of the NMAs, highlighting the missing relevant comparators (fluticasone furoate, bilastine, and rupatadine fumarate), which are funded by some participating drug plans, and the lack of appropriate representation of relevant comparators in the drug classes. At the reconsideration meeting, CDEC upheld their initial conclusions that they were unable to draw meaningful conclusions on the comparative efficacy of olopatadine-mometasone.
Adverse effects: Patients emphasized the need for reduced unpleasant side effects caused by current active treatments for seasonal allergic rhinitis. Based on the evidence from clinical trials, olopatadine-mometasone nasal spray raised no new safety concerns compared to placebo or mometasone nasal spray. During the reconsideration meeting, CDEC further discussed the numerically higher rates of dysgeusia with olopatadine-mometasone, as this is a known side effect of olopatadine. CDEC and the clinical experts highlighted that while dysgeusia rates were low in the pivotal trials, they were still numerically greater than placebo and mometasone alone, although it was noted by the clinical experts that this would not limit the use of olopatadine-mometasone in practice. There were no harms evaluated in the sponsor-submitted NMAs; thus, CDEC was unable to determine the comparative safety versus other active treatments for seasonal allergic rhinitis.
HRQoL: CDEC noted that patients and clinicians highlighted improvement in HRQoL as an important outcome of treatment for patients with seasonal allergic rhinitis. In the clinical trials, no clinically meaningful improvement in HRQoL was identified in adolescents and adults in the Rhinoconjunctivitis Quality of Life Questionnaire – Standardized Activities (RQLQ[S]) overall score between olopatadine-mometasone nasal spray versus mometasone nasal spray, or in children with seasonal allergic rhinitis as assessed by the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) overall score between olopatadine-mometasone nasal spray versus placebo. As noted, there were no HRQoL outcomes assessed in the indirect treatment comparisons (ITC), and the comparative effect on HRQoL of olopatadine-mometasone versus other active treatments for seasonal allergic rhinitis remains unknown.
Generalizability: CDEC noted that none of the 3 clinical trials used the term moderate to severe to define the disease severity in the trial eligibility criteria, rather morning rTNSS and congestion scores were used to determine disease severity. However, CDEC and the clinical experts noted that disease severity generally relies on a clinician’s judgment based on the extent to which patients are impacted by their symptoms. Furthermore, CDEC and the clinical experts consulted for this review noted that the 14-day treatment duration used in the 3 clinical 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. This issue was also discussed at the reconsideration meeting and CDEC upheld their initial conclusion.
Allergic rhinitis, categorized as seasonal allergic rhinitis or perennial allergic rhinitis, is an immunoglobulin E-mediated inflammation of the nasal mucosa triggered by exposure to allergens. Seasonal allergic rhinitis accounts for approximately 76.7% of allergic rhinitis cases. The estimates of prevalence of seasonal allergic rhinitis in Canada range from 12.9% to 19.2% and affect approximately 3.5 million people in Canada. Patients often describe 1 or more of the following symptoms of allergic rhinitis: nasal congestion (stuffiness), nasal itching, rhinorrhea, sneezing, and cough. Allergic rhinitis is often accompanied with allergic conjunctivitis which includes ocular symptoms such as itchiness, redness, or irritation of the eye.
According to the clinical experts, management of moderate-to-severe seasonal allergic rhinitis involves a comprehensive approach, with the goals of alleviating symptoms, improving quality of life, and minimizing symptom exacerbations. 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 alone or in combination with intranasal antihistamine are considered first-line treatment options for moderate-to-severe seasonal allergic rhinitis and generally preferred to oral antihistamines alone. Oral antihistamines are also used to manage itching, sneezing, and ocular symptoms, and would be considered as adjunctive therapy. Leukotriene receptor antagonists can be considered for the treatment of allergic rhinitis, particularly in patients who have concomitant asthma or those who do not respond adequately to other therapies. Other pharmaceutical therapies that can be used in patients with allergic rhinitis include ocular antihistamines, mast cell stabilizers as well as 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.
Ryaltris has been approved by Health Canada for the symptomatic treatment of moderate-to-severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older. Ryaltris contains both olopatadine hydrochloride and mometasone furoate, which represent histamine H1-receptor antagonist and synthetic corticosteroid, respectively. It is available as suspension for nasal spray and the dosage recommended in the product monograph is 2 sprays in each nostril twice daily (morning and evening) for adults and adolescents (aged 12 years and older) or 1 spray per nostril twice daily (morning and evening) for children (aged 6 to 11 years).
To make its recommendation, the committee considered the following information:
a review of 2 pivotal, phase III, double-blind, randomized active-controlled trials in adult and adolescent patients (aged 12 years and older) with seasonal allergic rhinitis (GSP301-301 and GSP301-304 trials); 1 pivotal, phase III, double-blind, randomized placebo-controlled trial in children (aged 6 to 11 years) with seasonal allergic rhinitis (GSP301-305 trial); and 2 ITCs
patients’ perspectives gathered by 2 patient groups, Asthma Canada and Allergy Quebec
2 clinical specialists with expertise diagnosing and treating adult or pediatric patients with seasonal allergic rhinitis
input from public drug plans that participate in the reimbursement review process
a review of the pharmacoeconomic model and report submitted by the sponsor
information submitted as part of the sponsor’s request for reconsideration (described subsequently)
feedback on the draft recommendation.
This review received 2 patient group input 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 their 2024 Annual Asthma Survey (total N = 1,407 patients and caregivers, of whom 37% reported experiencing allergic rhinitis as a comorbidity of their asthma, and 63% reporting having had an experience of seasonal allergic rhinitis). Asthma Canada also conducted 2 one-on-one interviews with patients with allergic rhinitis who were selected at random from the participants who completed the allergic rhinitis section of the survey and provided their contact information. Allergy Quebec did not perform any data collection from patients.
Both patient groups noted that allergic rhinitis 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, which negatively impact patients’ daily activities and quality of life. In total, 82% of survey responders indicated that the physical symptoms are the most difficult and/or frustrating aspect of living with allergic rhinitis. Patients stated that finding a solution and/or treatment to eliminate or significantly lessen the symptoms of allergic rhinitis 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. Based on the survey data from Asthma Canada, 43% of participants reported that their current treatments can, or most of the time, control their 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, and the undesired side effects (e.g., drowsiness, stuffiness, or dry nose), as well as cost and accessibility problems (e.g., lack of coverage or availability at local pharmacies) of some antihistamines.
According to the clinical experts consulted by the review team, the main goals of management of moderate-to-severe seasonal allergic rhinitis included 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 currently available treatments, particularly intranasal corticosteroids and oral antihistamines. Patients can also become refractory to current treatment options over time (e.g., due to escalation of eosinophilic inflammation that would not respond to first-line treatment with antihistamines). The clinical experts also noted the need for treatment options that offer better tolerability, and that 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 combining an intranasal corticosteroid with an antihistamine. The clinical experts consulted by the review team noted that in clinical practice intranasal corticosteroids alone are usually provided to patients first since 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 as the combination therapy is generally more costly, requires twice daily administration, and may not be tolerated due to taste. 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, patients most suitable or most likely to respond to olopatadine-mometasone include those who are experiencing moderate-to-severe symptoms of seasonal allergic rhinitis, those who have had inadequate response to monotherapy with intranasal corticosteroids or with antihistamines, and those who require both anti-inflammatory (intranasal corticosteroids) and antihistaminic or mast cell stabilizing effects to effectively manage their symptoms; and patients whose quality of life is significantly impacted by seasonal allergic rhinitis symptoms, affecting daily activities, sleep, and overall well-being. According to the clinical experts consulted by the review team, olopatadine-mometasone would be identified for these patients via clinical evaluation and symptom assessment and the assessment of symptom severity would occur through patient history and physical examination. Conversely, patients least suitable for olopatadine-mometasone include those with mild symptoms of seasonal allergic rhinitis 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 immunoglobulin E testing, can identify allergens triggering symptoms but is not required specifically for 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 typical outcomes used 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 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, 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 discontinuation of olopatadine-mometasone should be considered, including lack of effectiveness, intolerable or persistent adverse events, 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 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 seasonal allergic rhinitis, monitor treatment response through regular follow-up visits, and adjust therapy as needed. According to the clinical experts consulted by the review team, while specialists, such as allergists and immunologists or otolaryngologists, may offer additional expertise in managing severe or refractory cases of allergic rhinitis, their involvement is not always required for routine diagnosis and management with olopatadine-mometasone.
No clinician group input was received by the review team for this review.
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 Ryaltris:
relevant comparators
consideration for initiation of therapy
consideration for prescribing of therapy
generalizability
system and economic issues.
The clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs.
Three sponsor-conducted pivotal studies, GSP301-301, GSP301-304, and GSP301-305, were included in the sponsor-submitted systematic literature review (SLR). Both GSP301-301 (N = 1,176) and GSP301-304 (N = 1,180) were phase III, double-blind RCTs which enrolled adolescent and adult patients (aged 12 years and older) with seasonal allergic rhinitis. The primary objective of the GSP301-301 and GSP301-304 trials was to compare the efficacy of olopatadine-mometasone with placebo and individual constituent monotherapies (i.e., olopatadine hydrochloride nasal spray and mometasone nasal spray) at the same dose in the same vehicle, as well as assessing the efficacy of olopatadine hydrochloride nasal spray and mometasone nasal spray versus placebo over 14 days of study treatment. Olopatadine hydrochloride nasal spray is currently unavailable in Canada, and thereby not relevant to this reimbursement review. Results for olopatadine hydrochloride nasal spray were not presented in the clinical review report. GSP301-305 (N = 446) was a phase III, double-blind, RCT investigating children (aged ≥ 6 to < 12 years) with seasonal allergic rhinitis. 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 rTNSS. Secondary efficacy and safety outcomes reported in the 3 pivotal trials included patient-reported 12-hour iTNSS, patient-reported 12-hour rTOSS, and harms (i.e., TEAEs, TESAEs, withdrawals, deaths). HRQoL outcomes evaluated in the trials included the RQLQ(S) in the GSP301-301 and GSP301-304 trials, and the 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%). In the GSP301-301 trial, the baseline rTNSS score was the same across the olopatadine-mometasone group, the mometasone nasal spray 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 nasal spray 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 were 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.
In the full analysis set (FAS) of the GSP301-301 trial, the within-group least squares (LS) mean change from baseline in 12-hour rTNSS over the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ █████████ █████ ████ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, ███ █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in 12-hour rTNSS over the 14-day treatment period was −0.98 points (95% confidence interval [CI], −1.38 to −0.57 points) between the olopatadine-mometasone group and the placebo group, and −0.39 points (95% CI, −0.79 to 0.01 points) between the olopatadine-mometasone group and the mometasone nasal spray group, with both point estimates of 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 12-hour rTNSS versus the 14-day treatment period showed an improvement in all 3 treatment groups| █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, and █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in 12-hour rTNSS versus the 14-day treatment period was −1.09 points (95% CI, −1.49 to −0.69 points) between the olopatadine-mometasone group and the placebo group, and −0.47 points (95% CI, −0.86 to −0.08 points) between the olopatadine-mometasone group and the mometasone nasal spray group, with both point estimates of 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 12-hour rTNSS versus 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 12-hour rTNSS versus the 14-day treatment period was −0.6 points (95% CI, −0.9 to −0.2 points) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.
In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in 12-hour iTNSS versus the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, and █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in 12-hour iTNSS versus the 14-day treatment period was −0.93 points (95% CI, −1.28 to −0.58 points) between the olopatadine-mometasone group and the placebo group and −0.36 points (95% CI, −0.71 to −0.01 points) between the olopatadine-mometasone group and the mometasone nasal spray group, and both point estimates of 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 12-hour iTNSS versus the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, ███ █████ ██████ ███ █ ██) in the placebo group. The between-group LS mean difference in 12-hour iTNSS versus the 14-day treatment period was −0.94 points (95% CI, −1.32 to −0.56 points) between the olopatadine-mometasone group and the placebo group and −0.51 points (95% CI, −0.88 to −0.13 points) between the olopatadine-mometasone group and the mometasone nasal spray group, with both point estimates of 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 12-hour iTNSS versus 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 12-hour iTNSS versus the 14-day treatment period was −0.6 points (95% CI, −1.0 to −0.3 points) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.
In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in 12-hour rTOSS versus the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, ███ █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in 12-hour rTOSS versus the 14-day treatment period was −0.49 points (95% CI, −0.79 to −0.19 points) between the olopatadine-mometasone group and the placebo group and −0.19 points (95% CI, −0.49 to 0.11 points) between the olopatadine-mometasone group and the mometasone nasal spray group, and both point estimates of 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 12-hour rTOSS versus the 14-day treatment period showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, and █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in 12-hour rTOSS versus the 14-day treatment period was −0.52 points (95% CI, −0.84 to −0.20 points) between the olopatadine-mometasone group and the placebo group and −0.35 points (−0.66 to −0.03 points) between the olopatadine-mometasone group and the mometasone nasal spray group, and both point estimates of 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 12-hour rTOSS versus the 14-day treatment period showed an improvement in both treatment groups: | ████ ██████ ███ █ █████ in the olopatadine-mometasone group ███ ████ ██████ ███ █ █████ in the placebo group. The between-group LS mean difference in 12-hour rTOSS versus the 14-day treatment period was −0.2 points (95% CI, −0.6 to 0.1 points) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.
In the FAS of the GSP301-301 trial, the within-group LS mean change from baseline in RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, ███ █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in RQLQ(S) overall score at day 15 was −0.43 points (95% CI, −0.64 to −0.21 points) between the olopatadine-mometasone group and the placebo group and −0.20 points (95% CI, −0.41 to 0.02 points) between the olopatadine-mometasone group and the mometasone nasal spray 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 RQLQ(S) overall score at day 15 showed an improvement in all 3 treatment groups: █████ ██████ ███ █ ███ in the olopatadine-mometasone group, █████ ██████ ███ █ ███ in the mometasone nasal spray group, and █████ ██████ ███ █ ███ in the placebo group. The between-group LS mean difference in RQLQ(S) overall score at day 15 was −0.45 points (95% CI, −0.68 to −0.22 points) between the olopatadine-mometasone group and the placebo group and −0.09 points (95% CI, −0.32 to 0.14 points) between the olopatadine-mometasone group and the mometasone nasal spray 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 PRQLQ overall score at day 15 showed an improvement in all 3 treatment groups: ████ ██████ ███ █ █████ in the olopatadine-mometasone group and ████ ██████ ███ █ █████ in the placebo group. The between-group LS mean difference in PRQLQ overall score at day 15 was −0.3 points (95% CI, −0.5 to −0.1 points) between the olopatadine-mometasone group and the placebo group, which favoured the olopatadine-mometasone group.
In the safety analysis set of the GSP301-301 trial, the proportion of patients experiencing TEAEs was 12.9% (39 of 302) in the olopatadine-mometasone group, which was higher than that in the mometasone nasal spray group (7.1%, 21 of 294) or in the placebo group (9.4%, 27 of 287). The proportion of patients who had dysgeusia was 3.3% (10 of 302) in the olopatadine-mometasone group, 0.7% (2 of 287) in the placebo group, and 0 in the mometasone nasal spray group. Headache occurred in 2.8% (8 of 287) of the patients in the placebo group, higher than that in the olopatadine-mometasone group (0.7%, 2 of 302) or in the mometasone nasal spray group (0.7%, 2 of 294). █████████ ███ ████████ ██ ████ ███████ of the patients in the olopatadine-mometasone group, ██ ████ ███████ of the patients in the mometasone nasal spray 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 of 294) in the olopatadine-mometasone group, higher than that in the mometasone nasal spray group (9.6%, 28 of 293) or in the placebo group (9.5%, 28 of 294). Dysgeusia was reported in 3.7% of patients (11 of 294) in the olopatadine-mometasone group and 0 in the mometasone nasal spray group or in the placebo group. ████████ ████████ ██ ████ ███████ of the patients in the mometasone nasal spray group, in ████ ███████ of the patients in the placebo group, and 0 in the olopatadine-mometasone group. The proportion of patients who had epistaxis was 0.7% (2 of 294) in the olopatadine-mometasone group, 1.0% (3 of 293) in the mometasone nasal spray group, and 1.0% (3 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 of 225) in the olopatadine-mometasone group and 10.4% (23 of 221) in the placebo group. The most common TEAE in the olopatadine-mometasone group was epistaxis (2.3%, 5 of 225), while 0.9% of patients (2 of 221) in the placebo group had epistaxis. Dysgeusia were reported in 1.3% of patients (3 of 225) in the olopatadine-mometasone group and 0 in the placebo group. Headache occurred in 1.3% of patients (3 of 225) in the olopatadine-mometasone group and 0.5% of patients (1 of 221) in the placebo group.
In the safety analysis set of the GSP301-301 trial, only 1 patient had TESAE (0.3%) in the GSP301-301 trial, which was 1 spontaneous abortion in the olopatadine-mometasone group.
In the safety analysis set of the GSP301-304 trial, there were no patients who had TESAEs occur in the olopatadine-mometasone group. One patient (0.3%) had 1 TESAE (i.e., peritonsillar abscess) in the mometasone nasal spray group, and 1 patient (0.3%) had 3 TESAEs (including 1 osteomyelitis, 1 syncope, and 1 foot fracture) in the placebo group.
In the safety analysis set of the GSP301-305 trial, there was only 1 TESAE (i.e., meningitis) reported in 1 patient (0.5%) in the placebo group.
In the safety analysis set of the GSP301-301 trial, there were no patients who withdrew due to TEAEs in the olopatadine-mometasone group, while 4 in the mometasone nasal spray group and 1 in the placebo group withdrew due to TEAEs. Reasons for withdrawal were not reported.
In the safety analysis set of the GSP301-304 trial, there were no patients who withdrew due to TEAEs in the olopatadine-mometasone group or in the mometasone nasal spray group. One patient (0.3%) discontinued due to foot fracture in the placebo group.
In the safety analysis set of the GSP301-305 trial, there were 4 patients (1.8%) who withdrew due to TEAEs (including 1 conjunctivitis, 1 acute otitis media, 1 sinusitis, and 1 upper respiratory tract infection) in the olopatadine-mometasone group and 1 patient (0.5%) who had otitis media in the placebo group.
No deaths were reported in the GSP301-301, GSP301-304, or GSP301-305 trials.
The risk of bias arising from the randomization process was determined to be low for all 3 pivotal trials, including the GSP301-301 and GSP301-304 trials in adolescents and adults (aged 12 years and older) and in children (aged ≥ 6 and < 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 low by the review team as all 3 pivotal trials adopted the double-blind design, which masked the trial participants and trial personnel. An adherence rate between 75% and 125% (i.e., twice a day for 14 days to twice a day for up to 17 days) was achieved by more than 90% of patients in each treatment group. The risk of bias due to missing outcome data were 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 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 nonadherence to study protocol (defined as major protocol violation), and sensitivity analyses for rTNSS, which assumed the data missing was missing not at random showed consistent results to those from the FAS (results not reported) 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, as reflective and/or instantaneous symptom scales were primarily designed 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 context in Canada despite some potential issues. First, the Health Canada–approved indication is for patients with moderate-to-severe seasonal allergic rhinitis. 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 a rTNSS of greater than or equal to 8 out of a possible 12 and a congestion score of 2 or more at the morning assessment at the screening visit, and as patients with a rTNSS of greater than or equal to 6 out of a possible 12 and a congestion score of 2 or more at the morning assessment at the screening visit in the GSP301-305 trial. According to the clinical experts consulted by the review team, these symptom score cut-offs correctly reflect the moderate-to-severe disease severity and were appropriate in the clinical trial setting to define patients with moderate-to-severe seasonal allergic rhinitis. However, the clinical experts consulted by the review team also noted that in the clinical setting, the cut-off symptom scores 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. Second, the clinical experts consulted by the review team noted that from the perspective of the 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 patients they would see in the real world but 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 in the real world, which may overestimate the treatment effect that would be observed in a real-world setting.
Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers 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 rTNSS, iTNSS, rTOSS, RQLQ(S), and PRQLQ were set according to the presence of an important effect based on thresholds agreed upon by clinical experts consulted by the review team for this review. For harm events, the certainty of evidence was summarized narratively.
For the GRADE assessments, 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 and < 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.
Table 1 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for adolescent and adult patients (aged 12 years and older) with seasonal allergic rhinitis.
Table 3 presents the GRADE summary of findings for olopatadine-mometasone versus placebo for children (aged ≥ 6 years and < 12 years) with seasonal allergic rhinitis.
Table 2 presents the GRADE summary of findings for olopatadine-mometasone versus mometasone nasal spray for adolescent and adult patients (aged 12 years and older) with seasonal allergic rhinitis.
Table 1: Summary of Findings for Olopatadine-Mometasone Versus Placebo for Adolescent and Adult Patients (Aged 12 Years and Older) With Seasonal Allergic Rhinitis
Outcome and follow-up | Patients (studies), N | Effect | Certainty | What happens |
|---|---|---|---|---|
Nasal symptoms | ||||
12-hour rTNSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,163 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Higha | Olopatadine-mometasone results in a clinically important improvement in 12-hour rTNSS over 14 days compared to placebo. |
12-hour iTNSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,163 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Higha | Olopatadine-mometasone results in a clinically important improvement in 12-hour iTNSS over 14 days compared to placebo. |
Ocular symptoms | ||||
12-hour rTOSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,163 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderateb | Olopatadine-mometasone likely results in an improvement in 12-hour rTOSS over 14 days compared to placebo. |
HRQoL | ||||
RQLQ(S) overall score, LS mean change from baseline on day 15 (95% CI) Follow-up: Day 15 | N = 1,140 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderatec | Olopatadine-mometasone likely results in little-to-no difference in RQLQ(S) overall score at day 15 compared to placebo. |
Harms | ||||
TESAEs | N = 1,177 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderated | Olopatadine-mometasone likely results in little-to-no difference in TESAEs compared to placebo. |
CI = confidence interval; HRQoL = health-related quality of life; LS = least squares; MID = minimal important difference; NR = not reported; 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 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.
aCertainty of evidence was not rated down as there were no serious concerns in risk of bias, indirectness, inconsistency, and imprecision.
bImprecision was rated down for 1 level: According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 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.
cImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 0.5 points was considered clinically important (i.e., MID). The upper bound of the 95% CI of LS mean change from baseline in RQLQ(S) overall score in both the GSP301-301 and GSP301-304 trials crossed the MID, with point estimates favouring olopatadine-mometasone.
dImprecision was rated down for 1 level due to a small number of events.
Table 2: Summary of Findings for Olopatadine-Mometasone Versus Mometasone Nasal Spray Groups for Adolescent and Adult Patients (Aged 12 Years and Older) With Seasonal Allergic Rhinitis
Outcome and follow-up | Patients (studies), N | Effect | Certainty | What happens |
|---|---|---|---|---|
Nasal symptoms | ||||
12-hour rTNSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,177 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderatea | Olopatadine-mometasone likely result in little-to-no difference in 12-hour rTNSS over 14 days compared to mometasone nasal spray. |
12-hour iTNSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,177 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderateb | Olopatadine-mometasone likely results little-to-no difference in 12-hour iTNSS over 14 days compared to mometasone nasal spray. |
Ocular symptoms | ||||
12-hour rTOSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 1,177 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Lowc | Olopatadine-mometasone may result in little-to-no difference in 12-hour rTOSS over 14 days compared to mometasone nasal spray. |
HRQoL | ||||
RQLQ(S) overall score, LS mean change from baseline on day 15 (95% CI) Follow-up: Day 15 | N = 1,154 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Highd | Olopatadine-mometasone results in little-to-no difference in RQLQ(S) overall score at day 15 compared to mometasone nasal spray. |
Harms | ||||
TESAEs | N = 1,177 (2 RCTs) | GSP301-301 trial
GSP301-304 trial
| Moderatee | Olopatadine-mometasone likely result in little-to-no difference in TESAEs compared to mometasone nasal spray. |
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; 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 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.
aImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 12-hour rTNSS in the GSP301-301 and GSP301-304 trials included the MID, with point estimates favouring olopatadine-mometasone.
bImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 12-hour iTNSS in the GSP301-301 and GSP301-304 trials included the MID, with point estimates favouring olopatadine-mometasone.
cInconsistency was rated down for 1 level. The point estimate of the LS mean change from baseline in average morning and evening 12t-hour rTOSS was near 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. Imprecision was rated down 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 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.
eImprecision was rated down for 1 level due to small number of events.
Table 3: Summary of Findings for Olopatadine-Mometasone Versus Placebo for Children (Aged ≥ 6 Years and < 12 Years) With Seasonal Allergic Rhinitis
Outcome and follow-up | Patients (studies), N | Effect | Certainty | What happens |
|---|---|---|---|---|
Nasal symptoms | ||||
12-hour rTNSS, LS mean change from baseline in average morning and evening (95% CI) Follow-up: 14 days | N = 441 (1 RCT) | GSP301-305 trial
| Moderatea | Olopatadine-mometasone likely results in an improvement in 12-hour rTNSS over 14 days compared to placebo. |
12-hour iTNSS, LS mean change from baseline in average morning and evening. (95% CI) Follow-up: 14 days | N = 441 (1 RCT) | GSP301-305 trial
| Moderateb | Olopatadine-mometasone likely results in an improvement in 12-hour iTNSS over 14 days compared to placebo. |
Ocular symptoms | ||||
12-hour rTOSS, LS mean change from baseline in average morning and evening. (95% CI) Follow-up: 14 days | N = 441 (1 RCT) | GSP301-305 trial
| Moderatec | Olopatadine-mometasone likely result in little-to-no difference in 12-hour rTOSS over 14 days compared to placebo. |
HRQoL | ||||
PRQLQ overall score, LS mean change from baseline on day 15 (95% CI) Follow-up: Day 15 | N = 441 (1 RCT) | GSP301-305 trial
| Moderated | Olopatadine-mometasone likely results in little-to-no difference in PRQLQ overall score at day 15 compared to placebo. |
Harms | ||||
TESAEs | N = 446 (1 RCT) | GSP301-305 trial
| Moderatee | Olopatadine-mometasone likely results in little or no difference in TESAEs compared to placebo. |
CI = confidence interval; HRQoL = health-related quality of life; iTNSS = instantaneous Total Nasal Symptom Score; MID = minimal important difference; NR = not reported; PRQLQ = Pediatric Rhinoconjunctivitis Quality of Life Questionnaire; RCT = randomized controlled trial; rTNSS = reflective Total Nasal Symptom Score; rTOSS = reflective Total Ocular Symptom Score; TESAE = treatment emergent 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.
aImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 12-hour TNSS in the GSP301-305 trial included the MID, with point estimate favouring olopatadine-mometasone and excluding MID.
bImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 12-hour iTNSS in the GSP301-305 trial included the MID, with point estimate favouring olopatadine-mometasone and excluding MID.
cImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 morning and evening 12-hour rTOSS in the GSP301-305 trial included the MID, with point estimate favouring olopatadine-mometasone.
dImprecision was rated down for 1 level. According to the clinical experts consulted by the review team, a between-group difference of more than 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 PRQLQ overall score in the GSP301-305 trial included the MID, with point estimate favouring olopatadine-mometasone.
eImprecision was rated down for 1 level due to small number of events.
A long-term extension study which evaluated the long-term (52 weeks) safety, tolerability, and efficacy of olopatadine-mometasone in adults and adolescents (aged 12 years and older) with perennial allergic rhinitis was submitted by the sponsor. However, given that the Health Canada–approved indication is for the treatment of seasonal allergic rhinitis, not perennial allergic rhinitis, the long-term study submitted by the sponsor was not considered relevant to this review and was therefore not appraised.
The ITC submitted by the sponsor included 2 NMAs. One NMA evaluated the efficacy among olopatadine-mometasone compared to placebo, intranasal corticosteroids, and oral antihistamines in adolescent and adult patients (aged 12 years and older) with seasonal allergic rhinitis. The other NMA assessed the efficacy of olopatadine-mometasone relative to placebo and intranasal corticosteroids in children (aged ≥ 6 and < 12 years) with seasonal allergic rhinitis. 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 by 12-hour rTNSS in both NMAs.
In the base-case analysis, the mean and LS mean difference in 12-hour rTNSS was −1.26 points (95% CrI, −1.86 to −0.67 points) between the olopatadine-mometasone and placebo arms, −0.27 points (95% CrI, −0.87 to 0.33 points) between the olopatadine-mometasone and intranasal corticosteroids arms, and −0.91 points (95% CrI, −1.91 to 0.06 points) between the olopatadine-mometasone and oral antihistamines arms. Results from the sensitivity analyses were generally consistent with the results in the base-case analysis.
In the base-case analysis, the mean and LS mean difference in 12-hour rTNSS was −1.21 points (95% CrI, −1.86 to −0.56 points) between the olopatadine-mometasone and placebo arms and −0.94 points (95% CrI, −1.63 to −0.26 points) between the olopatadine-mometasone and intranasal corticosteroids arms. No sensitivity analyses were conducted.
Harms data were not examined in either NMA submitted by the sponsor.
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, which were approved by Health Canada for the treatment of seasonal allergic rhinitis, 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, missing relevant comparators from the SLR protocol might have resulted in missing evidence in the following NMAs, although the impact of this potential bias remained 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, 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 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 adolescent and adult NMA. In the children NMA, the intranasal corticosteroid node only consisted of mometasone and ciclesonide. The review team determined that 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.
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 which might be a potential source 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, inclusion of these variables was beyond the sponsor’s control given the limited availability of data in the included studies.
No studies addressing gaps in the pivotal and RCT evidence were submitted by the sponsor.
Table 4: Summary of the Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Decision tree |
Target population | Patients aged 6 years and older, experiencing an episode of moderate-to-severe seasonal allergic rhinitis |
Treatment | Olopatadine hydrochloride and mometasone furoate nasal spray suspension (olopatadine-mometasone), daily use during an episode of seasonal allergic rhinitis |
Dose regimen |
|
Submitted price | Olopatadine-mometasone: $56.11 per bottle (240 metered sprays) |
Submitted treatment cost | Children (6 to 11 years): $0.94 per day (4 sprays) Adolescent and adults (≥ 12 years): $1.87 per day (8 sprays) |
Comparators |
|
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs |
Time horizon | 28 days |
Key data sources | Efficacy of olopatadine-mometasone informed by the GSP301-301 and GSP301-304 trials for adolescents and adults (compared with placebo, mometasone), and by the GSP301-305 trial for children (compared with placebo). Efficacy of oral antihistamine and intranasal corticosteroid informed by sponsor-submitted NMAs. |
Key limitations |
|
CDA-AMC reanalysis results |
|
CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; NMA = network meta-analysis QALY = quality-adjusted life-year; SLR = systematic literature review.
aIn the economic model, the sponsor considered intranasal corticosteroid to be represented by mometasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate. Costing for this group was based on the least costly generic (mometasone furoate). Efficacy for oral antihistamines from the sponsor’s NMA for children was represented by mometasone and ciclesonide, with the assumption of that efficacy would be the same for all drugs in the class.
bIn the economic model, the sponsor considered oral antihistamines to be represented by cetirizine, desloratadine, fexofenadine, and loratadine. Costing for this group was based on the least costly generic (cetirizine). Efficacy for oral antihistamines from the sponsor’s NMA was represented by loratadine, with the assumption of that efficacy would be the same for all drugs in the class.
CDA-AMC identified the following key limitations with the sponsor’s analysis: the modelling approach used by the sponsor introduces uncertainty that could not be resolved. Additional limitations include uncertainty in the market uptake of olopatadine-mometasone and the presence of confidential prices for comparators.
The limitations of the modelling approach to estimate the incremental budget impact could not be addressed by CDA-AMC. Although the sponsor’s base-case estimates that the reimbursement of olopatadine-mometasone will be associated with incremental costs of $8,222,757 over 3 years (year 1: $1,958,164; year 2: $2,723,295; year 3: $3,541,293), the impact of reimbursing olopatadine-mometasone is highly uncertain.
The sponsor filed a request for reconsideration of the draft recommendation for olopatadine-mometasone for the symptomatic treatment of moderate-to-severe seasonal allergic rhinitis and associated ocular symptoms in adults, adolescents, and children aged 6 years and older. In their request, the sponsor identified the following issues:
The sponsor requested that CDEC consider the information from the Canadian Practice Parameter which states that intranasal antihistamine plus intranasal corticosteroid combination is preferred to intranasal corticosteroid plus oral antihistamine combination as first-line therapy for allergic rhinitis, and, according to the sponsor, supports the use of the intranasal antihistamine plus intranasal corticosteroid combination to address the current unmet need faced by patients.
The sponsor requested that CDEC revise their claims that there is no evidence that olopatadine-mometasone improves adherence, citing the rapid onset of action driven by olopatadine, which may improve adherence.
The sponsor requested that CDEC revise their claims concerning the duration of the pivotal trials as the 14-day methodology is supported by FDA and Health Canada guidance for allergic rhinitis.
The sponsor requested that CDEC remove statements that relevant comparators are missing (i.e., bilastine and rupatadine) as the sponsor notes that these are not publicly funded for allergic rhinitis.
The sponsor notes that claims of higher rates of dysgeusia are unfounded and unapplicable to olopatadine-mometasone and should be removed.
In the meeting to discuss the sponsor’s request for reconsideration, CDEC considered the following information:
information from the initial submission related to the issues identified by the sponsor
feedback from 2 clinical specialists with expertise in diagnosing and treating patients with seasonal allergic rhinitis
feedback on the draft recommendation from 1 patient group, Asthma Canada
feedback on the draft recommendation from the public drug plans that participate in the reimbursement review process
feedback on the draft recommendation from the sponsor.
All feedback received in response to the draft recommendation is available on the CDA-AMC website.
Dr. Peter Jamieson (Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.
Initial meeting date: November 27, 2024
Regrets: Two expert committee members did not attend.
Dr. Peter Jamieson (Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.
Reconsideration meeting date: March 27, 2025
Regrets: Four expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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