Dr Wytske Fokkens Academisch Medisch Centrum Divisie Neurozintuigspecialismen Polikliniek KNO Meibergdreef 9 1105 AZ Amsterdam The Netherlands
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.
This 2-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 23 centres across six European countries (Estonia, Latvia, Lithuania, Russia, Sweden and the Netherlands) during the 2005 European spring grass pollen allergy season. The study protocol was approved by the appropriate local ethics committees and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. As the beginning and length of the pollen season are dependent on local climate, pollen counts were monitored for each area before and throughout the study, and participating sites were allowed to randomize patients to the study only when local pollen levels indicated that the grass pollen season had started (with a guidance of at least 30 grains/m3).
Clinically symptomatic patients aged ≥12 years were eligible for inclusion, if they had a documented history of SAR (defined as onset and offset of nasal allergy symptoms during each of the past two grass pollen seasons), and either a positive skin prick test (wheal ≥3 mm larger than negative control) to grass pollen, or a positive in vitro test for specific IgE, within the 12 months prior to the study. Patients were excluded, if they had evidence of a severe physical nasal injury or obstruction, asthma, rhinitis medicamentosa, or any other chronic medical condition that could interfere with the course of the study. Furthermore, excluded were patients who had received any INS within 4 weeks of the first visit, any other corticosteroid within 8 weeks prior to the first visit, and any other medications that could affect the symptoms of SAR or the effectiveness of the study drug.
Study assessments and procedures
The study involved four visits: screening (visit 1, −5 to −21 days), randomization (visit 2, day 1), mid-treatment efficacy and safety evaluation (visit 3, day 8 ± 2) and final efficacy and safety evaluation (visit 4, day 15 ± 1). During the screening and the treatment periods, the severity of each patient’s nasal and ocular symptoms was assessed by diary card: instantaneous scores indicated the patients’ level of symptoms at the time of recording the score (just prior to taking the next dose each day, as a measure of 24-h duration of action); reflective scores were based on the symptoms experienced by the patient during the previous 12 h (morning and evening, the scores summed and averaged to give the daily reflective score). Each symptom was rated on a 4-point categorical scale [ranging from 0 (symptom is not present) to 3 (symptom is severe, causes interference with daily activities or sleep, and is difficult for the patient to tolerate)]. Patients were randomized to treatment, if they had an instantaneous total nasal symptom score (iTNSS) of ≥6 and a reflective nasal congestion score (rNCS) of ≥2 on the day of randomization; and averages on the reflective TNSS (rTNSS) of ≥6, on the rNCS of ≥2, and on the reflective total ocular symptom score (rTOSS) ≥4 over the preceding 4 days.
Randomized patients received 2 weeks’ treatment with either fluticasone furoate nasal spray 110 μg od or placebo nasal spray od. Symptom scores were recorded on a daily basis prior to morning dosing and then 12-h later. Instantaneous TNSS was evaluated at 4, 6, 8, 10 and 12 h after the first dose of the study medication to provide data for the onset of treatment effect, and then daily thereafter. Patients evaluated their overall response to therapy at the end of the study period by scoring their answer to the question ‘how would you rate the effectiveness of the double-blind study drug for relieving your AR symptoms over the entire treatment period?’ on a 7-point categorical scale (significantly, moderately or mildly improved, no change, mildly, moderately or significantly worse).
In addition, quality of life was assessed at baseline and after 2 weeks of treatment using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), a validated, 28-item, self-administered questionnaire that assesses quality of life over the preceding week (18). Each question is scored on an increasing impairment scale of 0–6, with higher scores indicating greater impairment of quality of life; a reduction in score of 0.5 or greater is considered a clinically important difference (19). Safety and tolerability were assessed at each visit by adverse event (AE) monitoring, clinical examination (including observation of vital signs, physical examination and nasal examination), electrocardiogram (ECG) monitoring and clinical laboratory tests.
The primary efficacy endpoint was mean change from baseline over the entire treatment period in daily rTNSS. Key secondary endpoints included mean change from baseline over the entire treatment period in morning predose iTNSS and daily rTOSS, and the overall evaluation of response to therapy, and were controlled for multiplicity (see below). The mean change from baseline in RQLQ was also controlled for multiplicity. Other secondary endpoints included iTOSS, daily reflective and instantaneous individual symptom scores, and time to onset of action.
Based on data from a previous study (17), a sample size of 144 patients per treatment group would detect a difference of 1.0 in the primary efficacy endpoint between active treatment and placebo with a 5% two-sided significance level and 90% power, assuming a standard deviation of mean change from baseline over the entire treatment period in daily rTNSS of 2.6 (17). The primary analysis method was the pairwise comparison of treatment groups (fluticasone furoate vs placebo) using an ancova with adjustments for baseline rTNSS, country, age and gender. Secondary efficacy measures involving diary data were analyzed using the same method. Overall evaluation of response to therapy was analysed using logistic regression, adjusting for age, gender and country. All efficacy assessments were carried out on the intent-to-treat (ITT) population (all randomized patients who received at least one dose of the study drug). The primary efficacy endpoint served as gatekeeper for the interpretation of treatment comparisons, and analyses were performed in a sequential manner to control for multiplicity across the key secondary endpoints and RQLQ as follows: (i) mean change from baseline over the entire treatment period in morning predose iTNSS; (ii) overall evaluation of response to therapy and (iii) mean change from baseline over the entire treatment period in daily rTOSS and mean change from baseline to endpoint in the overall score of the RQLQ were controlled at the 0.05 level by Hochberg’s method.
Patient clinical characteristics and demographics
Of the 425 screened patients, 285 (ITT population) were randomized to receive either fluticasone furoate 110 μg od (n =141) or placebo od (n =144) (Fig. 1). Demographic and clinical characteristics were similar between the two groups at baseline (Table 1). In total, 266 patients (93%) completed the study; 16 patients (11%) withdrew early in the placebo group compared with only three (2%) in the fluticasone furoate group. The withdrawals were predominantly because of lack of efficacy [placebo, nine patients (6%); fluticasone furoate, one patient (1%)], and a further two patients in the placebo group withdrew because of severe seasonal allergy.
Table 1. Baseline patient demographics and clinical characteristics
Placebo (n =144)
Fluticasone furoate 110 μg (n =141)
Total (n =285)
SAR, seasonal allergic rhinitis; rTNSS, reflective total nasal symptom score; iTNSS, instantaneous total nasal symptom score; rTOSS, reflective total ocular symptom score; iTOSS, instantaneous total ocular symptom score.
Gender, n (%)
Duration of SAR, n (%)
≥2 to <5 years
≥5 to <10 years
Total symptom score, mean (SD)
Nasal symptoms. Fluticasone furoate improved the rTNSS to a greater extent than placebo from the first day of treatment onwards (Fig. 2A). The mean change from baseline in daily rTNSS over the treatment period was significantly greater for fluticasone furoate than for placebo [−4.94 and −3.18, respectively; least square (LS) mean difference −1.757; P <0.001]. Improvements in morning predose iTNSS from baseline were also significantly greater in the fluticasone furoate group than in the placebo group (−4.50 and −2.60, respectively; LS mean difference −1.898; P <0.001; Fig. 2B). Assessment of the treatment effect on daily reflective and morning predose instantaneous scores for individual nasal symptoms showed that improvements in all four symptoms contributed equally to the overall improvement observed with fluticasone furoate vs placebo (Fig. 3). As a measure of onset of action, the LS mean change from baseline in iTNSS was numerically greater for fluticasone furoate than for placebo at all postdose time points assessed on day 1, but did not reach statistical significance until 24 h after treatment initiation (day 1 iTNSS treatment difference: −1.244, P <0.001). This significant difference for iTNSS was then maintained at all daily assessments throughout the 2-week study. These data were supported by scores from reflective measures; evening rTNSS on day 1, the first reflective measurement 12 h following the first dose, showed a statistically significant treatment difference compared with placebo (−0.970, P < 0.003), which was maintained for every subsequent reflective score through to day 14.
Ocular symptoms. Patients receiving fluticasone furoate had significantly greater improvements from baseline in rTOSS than those receiving placebo (Table 2). The mean change from baseline to study end in daily rTOSS was −3.00 in the fluticasone furoate group compared with −2.26 in the placebo group (LS mean difference −0.741; P <0.001). Significant improvements in ocular symptoms with fluticasone furoate vs placebo were also demonstrated for morning predose iTOSS (LS mean difference −0.764; P < 0.001) and for the individual ocular symptoms, each of which contributed to a similar extent to the total scores (P <0.001 for all comparisons; Table 2).
Table 2. Mean change from baseline over the entire treatment period in daily rTOSS, iTOSS and daily reflective and instantaneous individual ocular symptom scores (ITT population)
Placebo (n =144)
Fluticasone furoate 110 μg (n =141)
Placebo (n =144)
Fluticasone furoate 110 μg (n =141)
rTOSS, reflective total ocular symptom score; iTOSS, instantaneous total ocular symptom score; LS, least square; ITT, intent-to-treat.
Total ocular symptom score
LS mean change (SE)
LS mean difference
LS mean change (SE)
LS mean difference
LS mean change (SE)
LS mean difference
LS mean change (SE)
LS mean difference
Overall evaluation of patient response to treatment. Overall response to treatment was significantly better for fluticasone furoate-treated patients than for placebo-treated patients (P <0.001), with 67% of patients receiving fluticasone furoate reporting significant or moderate improvement, compared with 39% of patients receiving placebo; no patient reported worsening of symptoms with fluticasone furoate, whereas 10% of placebo recipients reported symptomatic worsening.
Quality of life. Overall RQLQ score was decreased by 2.23 points in fluticasone furoate recipients and 1.53 points in placebo recipients. A difference in mean scores of −0.700 (P <0.001 for fluticasone furoate vs placebo) between the treatment groups was considered clinically significant (based on a minimally important difference threshold of 0.5) (19). The minimally important difference was also achieved in the individual domains of activity limitations, sleep problems, practical problems, nasal symptoms, eye symptoms and emotional function, but not for non-nose/eye symptoms.
Safety and tolerability
Fluticasone furoate 110 μg od was well tolerated. The incidence of AEs was similar in the fluticasone furoate and placebo groups (17% and 16%, respectively). Headache was the most commonly reported AE (fluticasone furoate, 9%; placebo, 6%). The most common drug-related AE was epistaxis, which occurred at an incidence of 3% in the fluticasone furoate group and <1% in the placebo group (all episodes were of mild intensity with the exception of one patient in the fluticasone furoate group who had moderate epistaxis). There were no serious AEs. At treatment end, nasal examination findings (septum condition, mucosal crusting and mucosal bleeding) were similar to baseline for both groups. The incidence of laboratory abnormalities was low and changes in vital signs were minor and similar across both groups, with no ECG abnormalities reported.
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.
This study was funded by GlaxoSmithKline R&D Ltd (Study FFR103184). The authors thank the FFR103184 GSK global study team for their contribution and the editorial assistance of Susan Cheer, PhD and Anna Koundouris, PhD (employees of Innovex Medical Communications) in the development and author review of this manuscript.