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Patient preferences and sensory comparisons of three intranasal corticosteroids for the treatment of allergic rhinitis

Claus Bachert, MD, PhD* and Tarek El-Akkad, MD

Background: Although they have comparable safety and efficacy profiles, different intranasal corticosteroids possess different sensory/chemical properties that can be easily differentiated by patients, and which may influence their preference and compliance. Objective: We sought to compare patient assessments of sensory attributes of three intranasal corticosteroid sprays: triamcinolone acetonide aqueous (TAA), fluticasone propionate (FP), and mometasone furoate (MF). Methods: In a multicenter, randomized, double-blind, crossover study, 95 patients with allergic rhinitis rated 14 sensory items (100-point scales), product preference, and likelihood of compliance with treatment. Results: Immediately after administration, compared with MF, TAA was rated as having significantly better comfort during administration, less irritation, less odor strength, preferred odor, more moistness of nose/throat, milder taste (all P 0.001), and preferred taste (P 0.01). Compared with FP, TAA was rated as having significantly less odor strength, preferred odor (both P 0.001), more moistness of nose/throat (P 0.01), and milder taste (P 0.05). Two minutes after application, TAA was rated as having less aftertaste than FP (P 0.01) or MF (P 0.001), and produced significantly less irritation (FP P 0.05; MF P 0.01). Of patients, 54.7% said they would prefer a prescription of TAA over one for MF (24.2%; P 0.001) or FP (21.1%; P 0.001). More patients indicated that they would be more compliant with treatment if given the TAA prescription (67.4%) than if given a prescription with FP (54.7%) or MF (49.5%). Conclusion: Several of the TAA sensory attributes were preferred over those of MF and FP. Patient preference may play a role in enhancing treatment compliance. Such findings indicate that TAA nasal spray may be a better choice than MF or FP in the treatment of seasonal and perennial allergic rhinitis.
Ann Allergy Asthma Immunol 2002;89:292297.

INTRODUCTION Allergic rhinitis is a highly prevalent, chronic condition and is currently estimated to affect approximately 10 to 20% of the general population.1 4 According to National Center for Healthcare statistics, as many as 40 million Americans have allergic rhinitis, and it accounts for 32 million office visits and an estimated $2.7 billion in direct and indirect costs in the United States alone.5,6 In Europe, the direct medical treatment costs of illness for allergic rhinitis are estimated at 1.0 to 1.4 billion Eurodollars.7 However, these costs are likely to have been underestimated because of the frequent use of over-thecounter medications, the close association with concomitant conditions such as asthma, and the additional indirect societal costs related to lost productivity and quality of life. Effective treatment approaches for allergic rhinitis include allergen avoidance, immunotherapy, and pharmacologic intervention.5,8,9 Topical intranasal corticosteroids have proven to be highly successful for the treatment of the nasal symp-

* Department of Ear, Nose, and Throat, University Hospital, Ghent, Belgium. Aventis Pharmaceuticals, Bridgewater, New Jersey. Study was funded by an unrestricted educational grant from Aventis. Received for publication November 22, 2001. Accepted for publication in revised form April 3, 2002.

toms of allergic rhinitis. A number of international reports on the management of rhinitis support the use of intranasal corticosteroids for adults with moderate-to-severe allergic rhinitis.5,8 11 Triamcinolone acetonide (TAA), fluticasone propionate (FP), and mometasone furoate (MF) are commonly used intranasal corticosteroids in the treatment of allergic rhinitis.2,8,9,12,13 They can all be administered once daily using a nasal spray, and at recommended dosages, they exhibit no major differences in clinical efficacy or safety profiles in the treatment of allergic rhinitis.9,12,13 Table 1 summarizes the inactive ingredients contained in the commercial formulations of TAA (Nasacort AQ, Rhne-Poulenc Rorer, Collegeville, PA), FP (Flonase, GlaxoSmithKline, Research Triangle Park, NC), and MF (Nasonex, Schering, Kenilworth, NJ). Both FP and MF contain phenylethyl alcohol, unlike TAA, which has been specifically formulated to be both odorless and tasteless. Regular prophylactic use of intranasal corticosteroids is recommended for the effective, long-term management of the symptoms of allergic rhinitis.8,9 Patient compliance, therefore, would have a significant impact on the success or failure of such therapy. Patients acceptance and satisfaction with their treatment may be an important factor in gaining treatment compliance. This is particularly important in the selection of appropriate choices for therapies such as intranasal



Table 1. Excipients* Contained in the Commercial Formulations of Triamcinolone Acetonide Aqueous (Nasacort AQ), Fluticasone Propionate (Flonase), and Mometasone Furoate (Nasonex) Excipient Microcrystalline cellulose/carboxymethylcellulose sodium Sodium citrate Phenylethyl alcohol Benzalkonium chloride Citric acid Edetate disodium Dextrose Polysorbate 80 Glycerin TAA Yes FP Yes MF Yes

METHODS Study Design This was a multicenter, randomized, double-blind, crossover study conducted in Norway, Germany, and Switzerland between April and September 1999. Patients visited the clinic on two occasions: visit 1, an initial screening visit (day 7 to day 1), and visit 2 for randomization to and evaluation of medication (day 1). Between visits, patients were not permitted to use any corticosteroids, whether administered orally or nasally. In addition, no systemic or injectable depot (slow-release) corticosteroid drugs were allowed. At visit 2, patients were sequentially randomized to receive one of three intranasal corticosteroids: 1) TAA: two actuations (55 g/spray) in each nostril (total dose 220 g daily); 2) FP: two actuations (50 g/spray) in each nostril (total dose 200 g daily); and 3) MF: two actuations (50 g/spray) in each nostril (total dose 200 g daily). To eliminate any potential order effects, we used a randomization procedure that ensured the testing of the three products in each of six possible drug administration sequences an approximately equal number of times. Patients prepared for the product assessments both before and between treatments using a washout protocol as follows: (1) chewing unsalted crackers; (2) rinsing their mouth with room temperature water; and (3) sniffing a swatch of wool cloth. There was a 30-minute waiting period between the administration of each corticosteroid. To maintain blinding, the medication was concealed in a closed container and administered by a third party. In addition, patients were blindfolded before and during product administration. Patients, interviewers, and study investigators remained unaware of the test drug identity during both the administration and evaluation periods.

No No Yes No Yes Yes Yes No

No 0.25% Yes No No Yes Yes No

Yes 0.25% Yes Yes No No Yes Yes

* From product package inserts. TAA, triamcinolone acetonide aqueous; FP, fluticasone propionate; MF, mometosone furoate.

corticosteroids, which have comparable efficacy and safety profiles.2,8,9,12,13 Recent studies have shown that patients perceptions of intranasal corticosteroids are influenced not only by the effectiveness and safety of an agent, but also by its ease and comfort of administration and by sensory attributes.14,15 Therefore, it is important to consider the likelihood of patient acceptance of the available treatment options when prescribing intranasal corticosteroids. The primary objective of this study was to evaluate and compare patient assessments of specific sensory attributes (Table 2) of three intranasal corticosteroid sprays commonly prescribed for the treatment of allergic rhinitis: TAA, FP, and MF. Patients also rated the treatments for overall preference and predicted compliance.

Table 2. Items on the Nasal Spray Evaluation Questionnaire Scale Item Score Immediately after administration Overall comfort during administration Amount of medication run-down throat and nose Amount of irritation Strength of urge to sneeze Odor strength Liking of odor Strength of taste Bitter taste Liking taste Dry-versus-moist sensation Two minutes after administration Strength of aftertaste Amount of irritation Amount of medication run-down throat and nose Overall liking of product 0 Score 100

Not at all comfortable None at all None at all No urge at all No odor at all Dislike it an extreme amount No taste at all Not at all bitter Dislike it an extreme amount Extremely dry No aftertaste at all None at all None at all Dislike it an extreme amount

Extremely comfortable An extreme amount An extreme amount Extremely strong urge Extremely strong odor Like it an extreme amount Extremely strong taste Extremely bitter Like it an extreme amount Extremely moist Extremely strong aftertaste An extreme amount An extreme amount Like it an extreme amount



The study was approved by the Independent Ethics Committee or Institutional Review Board responsible for each center in each country. All patients provided written informed consent. Patient Population All participants in this trial were at least 18 years of age and had at least a 2-year history of allergic rhinitis (perennial or seasonal). All participants had documented positive responses to skin prick testing or radioallergosorbent test for at least one allergen (perennial or seasonal) prevalent in the geographic area and environment and to which they had continual exposure. Exclusion criteria included the following: patients of childbearing potential who had not used a reliable contraceptive method (intrauterine device or systemic contraceptive) for the previous 2 months; patients with interfering medical conditions or clinical findings; presence of nasal candidiasis, sinusitis, polyposis, or other nasal defects that could impair breathing; history of hypersensitivity to corticosteroids; use of medication that could affect symptoms of allergic rhinitis or sensory perceptions of test drugs; and use of any investigational drug within 30 days of the study. Assessments After exposure to each test product, an interviewer administered a nasal spray evaluation questionnaire. This questionnaire evaluated the acceptability of the drug and associated sensory perceptions immediately (10 items) and 2 minutes (4 items) after drug administration, using a 100-point scale rating (Table 2). A global preference score was also calculated; this was the sum of all objective individual scores from the nasal spray evaluation questionnaire, omitting item 14 (overall satisfaction with the product). Once all three test products had been administered and evaluated, the interviewer administered the overall nasal spray questionnaire, in which patients were asked to rank all three products from 1 (most prefer to be prescribed) to 3 (least prefer to be prescribed). Patients also rated their expected compliance with a prescription of each product (rated from 1 definitely comply with prescription to 4 definitely not comply with prescription). Statistical Analysis Statistical analysis was performed on the intent-to-treat (ITT) population. This was defined as all patients who received at least one actuation of the study drug and had no unreliable data. Patients with unreliable data were those related to the investigator or those with violation of the treatment order. Mean scores ( standard deviation) for the nasal spray evaluation questionnaire and the calculated overall rating for the three nasal sprays were generated. To ensure that the order of administration did not significantly affect product ratings, an analysis of variance of the crossover design was used. First, a three-factor model (subject, treatment, and administration order) was used. The two-factor model (subject and treatment) was then used if all other effects were nonsignificant.

Patient overall ranked preferences for the three products and expected compliance were compared using a Cochran-Mantel-Haenszel test (preference frequencies by treatment controlling for subject). Safety The safety assessments were based on clinical examination by the investigator and the recording of adverse events. A physical examination was conducted and vital signs were measured at the screening visit (visit 1) and at the end of study (visit 2). Patients were questioned regarding adverse events that had occurred since the first visit, and these were recorded on the case report form. The safety population was defined as all patients who received at least one actuation of the study drug. RESULTS Subjects A total of 109 patients was randomized to receive treatment. Of these, 95 patients (82.6%) were included in the ITT population. Patients were eliminated from the ITT population as a result of violation of the treatment administration order (10 patients) or protocol deviations (4 patients). Thirty-six of the patients included in the ITT analysis were in Germany, 32 were in Switzerland, and 27 were in Norway. Baseline characteristics for the ITT population are shown in Table 3. Approximately equal numbers of patients were assigned to each of the treatment-order groups, and patient characteristics were comparable among groups. The mean patient age was 33.5 10.4 years (range: 17 to 69 years of age), and the majority of patients were white (91 of 95). Physical examination was normal in 90 of 95 of patients. Approximately half of patients (49 of 95) reported a history of significant illness, surgical procedures, and/or concomitant medical conditions. Assessments Nasal spray evaluation questionnaire. Statistical testing revealed that the order in which the drugs were administered did not affect product ratings; therefore, between-product statistical analysis of variance comparisons were undertaken. Mean sensory ratings of the 14 items of the nasal spray evaluation questionnaire for each test drug are presented in Figure 1. Analysis of the mean attribute ratings indicated several statistically significant between-product differences. Immediately after study drug administration, the strongest statistically significant differences identified were product odor and taste. Patients preferred the odor of TAA and judged it to be less strong compared with FP and MF (P 0.001). Similarly, the taste of TAA was judged to be less strong than that of either FP (P 0.05) or MF (P 0.001), and the taste of TAA was preferred over that of MF (P 0.01). In addition, immediately after administration, TAA produced a sensation of greater moisture than FP (P 0.01) or MF (P 0.001), which provided more comfort and less irritation during administration than MF (P 0.001). FP was



Table 3. Patient Baseline Characteristics Characteristic Sex Males Females Mean ( SD) age (years) Range (years) Race White Other Allergic rhinitis characteristics Type Perennial Seasonal Both Diagnostic test Skin prick RAST None Main symptoms Nasal discharge Itchy nose Sneezing Nasal congestion Prior medications Antihistamine Nasal corticosteroid Cromone Antileukotriene At least one (any type) Concomitant medications Antileukotriene Bronchodilator Inhaled corticosteroid At least one (any type) RAST, radioallergosorbent test. n (%) 50 (53%) 45 (47%) 33.5 ( 10.4) 1769 91 (96%) 4 (4%)

prescription of TAA over MF (24.2% [23 patients]; P 0.001) or FP (21.1% [20 patients]; P 0.001). The number of patients who would comply definitely with the prescription was greater for TAA (67.4% [64 patients]) than for FP (54.7% [52 patients]) and MF (49.5% [47 patients]). The statistical significance of these differences is not known. Safety Only one patient experienced an adverse event (mild dizziness) that was thought to be possibly drug-related (MF). No serious adverse events were reported throughout the study. In addition, no clinically significant changes in vital signs were observed during this study, and no statistically significant differences among the treatment groups were observed. DISCUSSION The results of this multicenter, randomized, double-blind study indicated that patients prefer intranasal TAA over MF and FP with respect to acceptability of product and influence on sensory perceptions. In particular, patients favored TAA with regard to treatment irritation, odor, taste, and overall product liking. Twice as many patients preferred a prescription of TAA versus FP and MF, and two-thirds of all patients in the study indicated that they would be more likely to comply with the TAA prescription. Only approximately half of all patients said they would comply with a prescription of either FP or MF. This trial focused on the short-term evaluation of product sensory attributes and did not evaluate long-term efficacy or safety. The nasal spray evaluation questionnaire used in this study has been used in a similar double-blind, randomized, crossover study involving 94 patients with allergic rhinitis.14 In a study by Gerson et al,14 TAA was compared with FP and beclomethasone dipropionate (BDP). In that study, as well as in the present one, the greatest differences identified among the treatment drugs were those of odor and taste, with TAA demonstrating statistically significantly better scores in both categories compared with other products. In the present study, the overall liking score indicated patient preference for the sensory attributes of TAA over both FP and MF. Similarly, Gerson et al14 showed that the overall liking of medication was significantly higher for TAA than for FP (P 0.05). These results are further confirmed by those of a 3-week randomized study comparing TAA with BDP in 152 adult patients with seasonal allergic rhinitis.15 In that study, patients rated TAA as having a statistically significantly preferable taste and odor compared with BDP (P 0.05). The evaluation performed immediately after administration revealed greater run-off with TAA versus FP or MF. This initial perception, also supported by the significantly higher moistness score seen with TAA, may be partially attributed to the absence of alcohol in the TAA formulation. It is possible that the alcohol contained within the FP and MF formulations contributed to the initial feelings of dryness and reduced run-off compared with TAA.

12 (13%) 46 (48%) 37 (39%) 69 (73%) 23 (24%) 3 (3%) 60 (63%) 44 (46%) 59 (62%) 70 (74%) 40 (42%) 38 (40%) 13 (14%) 13 (14%) 75 (79%) 7 (7%) 5 (5%) 3 (3%) 37 (39%)

also rated statistically significantly better than MF in terms of comfort during administration, amount of irritation, and taste (P 0.05). Immediately after administration, patients perceived that more TAA ran down their nose and throat (P 0.05) compared with both FP and MF. However, no statistically significant difference was found between treatments in medication run-off 2 minutes after administration, at which point TAA was rated as having less aftertaste than FP (P 0.01) or MF (P 0.001), and having produced significantly less irritation (FP, P 0.05; MF, P 0.01). There were no significant rating differences between MF and FP. Overall, patients indicated a preference (patient overall liking) for TAA over both FP (P 0.05) and MF (P 0.001). The overall evaluation of patient preference using the global preference score produced similar results, with TAA again ranked statistically significantly higher than either FP (P 0.035) or MF (P 0.001). Overall nasal spray questionnaire. Overall, 54.7% (52 of 95) of patients answered that they would most prefer a



Figure 1. Mean nasal spray evaluation questionnaire ratings: 14 items rated on a 100-point scale by the patient after administration of each product. Significance: TAA vs MF, *P 0.05, **P 0.01, ***P 0.001. TAA vs FP P 0.05, P 0.01, P 0.001. FP vs MF, P 0.05.

In most clinical trials, patient impressions of treatment are neglected. Unless a report of taste, odor, or irritation is linked to an adverse event or withdrawal, the patients sensory experience of the product is usually overlooked or even ignored. Further, when evaluated, patient sensory perceptions are often included in one overall patient preference rating that must also reflect the patients overall satisfaction with longterm product efficacy. However, patient perceptions of sensory attributes such as those evaluated in this study and patient overall preference for medication may be an important factor in gaining patient compliance. In this study, more than twice as many patients reported that they would prefer to be prescribed TAA compared with either FP or MF. Further, two-thirds of all patients in the study indicated that they were more likely to comply with the TAA prescription, compared with only half of all patients who would comply with the prescription of either FP or MF. This indicates a possible positive correlation between greater patient preference for TAA and greater compliance with treatment, at least over the short-term. In conclusion, this study demonstrated that, of the three intranasal corticosteroids evaluated, TAA was preferred over MF and FP, particularly in terms of product attributes: amount of irritation, odor, taste, and overall liking of product. In addition, twice as many patients preferred to be prescribed TAA, and the number of patients who stated that they would comply with the prescription was greater for TAA than for MF or FP. It is therefore likely that this drug may improve patient compliance and thus enhance treatment outcomes. Such findings indicate that TAA nasal spray may be preferred to MF or FP in the treatment of seasonal and perennial allergic rhinitis.

ACKNOWLEDGMENTS We acknowledge the significant contributions made by Dr. Gumowski, Hopital de la Tour, Meyrin, Switzerland, and Dr. Nerheim, Allergiklinikken, Bekkestua, Norway. REFERENCES
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Requests for reprints should be addressed to: Professor Claus Bachert University Hospital Department of ENT De Pintelaan 185 B9000 Ghent, Belgium E-mail: Claus.bachert@rug.ac.be

Answers to CME examinationAnnals of Allergy, Asthma, and Immunology, September 2002 Tan RA: Exercise-induced asthma: diagnosis and management. Ann Allergy Asthma Immunol 2002:89;226 236. 1. d 2. d 3. e 4. e 5. f