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Background: Fluticasone furoate is a new enhanced-affinity glucocorticoid with a unique combination of pharmacodynamic and physicochemical properties suitable for topical activity.
Methods: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, patients [adults and adolescents ≥12 years of age with seasonal allergic rhinitis (SAR)] received once-daily (od) treatment for 2 weeks with either fluticasone furoate nasal spray 110 μg (n = 141) or placebo nasal spray (n = 144) administered in a unique, side-actuated device. Efficacy measures included total nasal symptom score (TNSS) and total ocular symptom score (TOSS). Patients also reported their overall response to therapy and rated their quality of life using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ).
Results: Fluticasone furoate significantly improved the mean change from baseline in daily reflective TNSS compared with placebo (treatment difference of −1.757; P < 0.001). Fluticasone furoate was also significantly more effective in improving the morning predose instantaneous TNSS (treatment difference of −1.898; P < 0.001) and daily reflective TOSS (treatment difference of −0.741; P = 0.001). A significant treatment effect was observed as early as day 1. Compared with placebo-treated patients, fluticasone furoate-treated patients showed significantly greater improvements in overall evaluation of response to therapy (P < 0.001), as well as in overall RQLQ score (P < 0.001). Fluticasone furoate was well tolerated.
Conclusion: Fluticasone furoate nasal spray 110 μg od was effective in improving the nasal symptoms of SAR. It also produced significant improvements in ocular symptoms.
Allergic rhinitis (AR) is a common atopic condition that may include nasal and ocular symptoms (1, 2). Typical symptoms include nasal itching, sneezing, rhinorrhoea, nasal congestion and ocular itching/burning, tearing and redness (1, 2). Symptoms of AR can have detrimental effects on quality of life, emotional well-being, sleep and daytime performance and productivity (3–7). The burden of illness (8), combined with increasing prevalence (2) and economic impact (9), means that AR can be considered a major public health problem.
A number of pharmacological interventions exist for the treatment of AR (10). Of these, intranasal corticosteroids (INS) are effective in relieving the nasal symptoms of AR, including nasal congestion (11, 12). Guidelines for the management of AR recommend INS as first-line therapy when nasal congestion is a major symptom (13), or for patients with moderate-to-severe symptoms (1). Oral antihistamines achieve a degree of efficacy against symptoms mediated by histamine (rhinorrhoea, sneezing and nasal itching), but are less effective against nasal congestion (14). They have some effect on ocular symptoms and may be used concomitantly with INS in patients for whom ocular symptoms are troublesome. In a meta-analysis of studies comparing INS with antihistamines, INS treatment was shown to reduce ocular symptoms as effectively as oral antihistamines (15). However, evidence of consistent efficacy of an individual INS on ocular symptoms across a range of placebo-controlled studies has not previously been published.
Fluticasone furoate is a new enhanced-affinity glucocorticoid with a combination of pharmacodynamic and physicochemical properties that make it suitable for topical administration. It has been developed for the treatment of AR, administered via a unique, side-actuated device. Preclinical studies have demonstrated that it has greater affinity for the glucocorticoid receptor than several currently available INS (16). Intranasal fluticasone furoate also has low systemic bioavailability (0.5%), and in a 2-week dose-ranging study, once-daily (od) doses of 55–440 μg were well tolerated and significantly more effective than placebo in improving nasal symptom scores over 24 h (17), with 110 μg selected as the optimal dose. In addition, fluticasone furoate had a beneficial effect on ocular symptoms (17). The primary objective of this study was to investigate efficacy and tolerability of fluticasone furoate nasal spray 110 μg od compared with placebo nasal spray od in adults and adolescents aged ≥12 years with seasonal allergic rhinitis (SAR) during the European grass pollen season.
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This study demonstrated that the new enhanced-affinity glucocorticoid fluticasone furoate 110 μg od significantly improved the nasal symptoms of SAR (congestion, itching, rhinorrhoea and sneezing) during the grass pollen season (May–August) in Europe in adults and adolescents aged ≥12 years. Efficacy was also demonstrated for the relief of ocular symptoms (watering/tearing, itching/burning and redness). Although patients were recruited into the study when pollen counts were sufficiently high to cause AR symptoms, there was a gradual decrease in pollen counts over the treatment period, which may explain the continued improvement of nasal symptoms in patients receiving placebo. Nonetheless, compared with placebo, significant improvements in rTNSS with fluticasone furoate were maintained from day 1 throughout the treatment period to day 14.
In support of findings from a dose-ranging study (17), as well as the results of two other studies with fluticasone furoate nasal spray in adults and adolescents with SAR (20, 21), data from the current trial confirm that fluticasone furoate was effective in reducing ocular symptom scores in addition to relieving nasal symptoms. Evidence of consistent efficacy of individual INS on ocular symptoms across a range of placebo-controlled studies has not previously been published. The 2001 Allergic Rhinitis and its Impact in Asthma guidelines recommended the addition of oral or topical antihistamines to INS for the treatment of conjunctivitis related to SAR (1). Indeed, a study looking at currently available treatments found that most patients used two or more pharmacological agents to effectively manage the nasal and ocular symptoms of SAR (22). The availability of medication with dual efficacy in the treatment of both ocular and nasal symptoms of SAR may reduce the need for polypharmacy, and thus represents a potential therapeutic advance in the management of SAR.
The mechanism by which INS alleviate the ocular symptoms of SAR has yet to be fully elucidated. Possible mechanisms include: reduced inflammation in the nose resulting in reduced release of inflammatory mediators and, hence, less activation of inflammatory cells in the neighbouring tissues; improved drainage away from the eye down the nasolacrimal duct; and modulation of a naso-ocular neurogenic reflex. Further research will be required to clarify this. It is unlikely that the observed effect of fluticasone furoate on ocular symptoms results from systemic action either through absorption into the nasal mucosa or absorption of small amounts of swallowed drug. Intranasal fluticasone furoate has a low absolute bioavailability (0.50%), resulting from poor aqueous solubility, limited mucosal contact time with the nose, and extensive first-pass metabolism (23). Furthermore, fluticasone furoate has no effect on 24-h urinary cortisol and has not been associated with any adverse reactions that are suggestive of clinically relevant systemic exposure (17).
Results from this study suggest that the onset of action of fluticasone furoate occurs within the first day of treatment. Although statistical significance was not achieved at 12 h postdose for iTNSS, the LS mean change from baseline was numerically greater for fluticasone furoate than for placebo at all time points during the first 12 h following treatment administration. Furthermore, the first reflective measurement 12 h following the first dose (PM rTNSS on day 1) showed a statistically significant benefit for fluticasone furoate over placebo. Duration of treatment effect over the full 24-h dosing period was demonstrated by the significant reduction in morning predose iTNSS and iTOSS for fluticasone furoate compared with placebo, thus confirming the adequacy of od dosing, as demonstrated in other studies with fluticasone furoate nasal spray (17, 20, 21). Established INS, such as fluticasone propionate and mometasone furoate, are licensed for od administration based on the assessment of average reflective symptom scores over the course of a day, without determination of efficacy 24 h after dosing. In contrast, the inclusion of predose iTNSS and iTOSS in the present study directly evaluated efficacy 24 h after dosing.
The symptoms of SAR have been shown to have a significant impact on quality of life; therefore, any improvements in quality of life should help to reduce disease burden (5). Patients randomized to fluticasone furoate therapy experienced significant and clinically relevant improvement in the formal assessment of quality of life (as evidenced by RQLQ scores). In addition, at the end of this study, 67% of fluticasone furoate patients reported significant or moderate improvement in their overall evaluation of response to therapy, compared with 39% in the placebo group. The safety and tolerability findings of this study are consistent with those from other published studies (17, 20) and show that fluticasone furoate is well tolerated. Mild episodic epistaxis was the most common drug-related AE. In conclusion, daily treatment for 2 weeks with fluticasone furoate nasal spray 110 μg od was effective in improving the nasal symptoms of SAR. Significant improvements in ocular symptoms and in quality of life were also demonstrated. Based on these findings, and paired with a good safety and tolerability profile, fluticasone furoate nasal spray 110 μg od may represent a single treatment option for the symptoms of SAR.