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Comparative efficacy, safety, and effect on quality of life of triamcinolone acetonide and fluticasone propionate aqueous nasal sprays in patients with fall seasonal allergic rhinitis
Comparative efficacy, safety, and effect on quality of life of triamcinolone acetonide and fluticasone propionate aqueous nasal sprays in patients with fall seasonal allergic rhinitis Gary Gross, MD*; Robert L. Jacobs, MD†; Thomas H. Woodworth, BA‡; George C. Georges, MD‡; and Janet C. Lim, MD§
Background: The topical potency of fluticasone propionate (FP) is known to be four times greater than that of triamcinolone acetonide (TAA). However, the significance of this difference has not been proven in the clinical treatment of seasonal allergic rhinitis (SAR). Objective: To compare the efficacy, safety, and effect on health-related quality of life (HRQL) of FP and TAA aqueous nasal sprays in patients with SAR Methods: Single-blind, parallel-group, active-controlled design. Patients were randomized to 3-week treatment with TAA 220 g (n ⫽ 172) or FP 200 g (n ⫽ 180) as two sprays/nostril once daily AM. Twelve-hour reflective symptom evaluations (nasal discharge, stuffiness, itching; sneezing; ocular itching/tearing/redness) were performed AM/PM, beginning at pretreatment baseline period. Incidences of specific treatment-related side effects were collected in daily questionnaires. HRQL was evaluated at baseline and end-of-treatment with a validated disease-specific, quality-of-life instrument. Results: TAA and FP produced similar improvement in daily total nasal symptom scores overall (49.4% and 52.7%, respectively; P ⫽ 0.332) and at every weekly time point (P ⬎ 0.05). There were no significant differences between TAA and FP in any individual symptom score at any time point except week 2 (FP provided greater reduction in sneezing, P ⫽ 0.046). No significant difference was found between groups in overall occurrence of specific treatment-related side effects. Overall Rhinoconjunctivitis Quality of Life Questionnaire scores were similar for TAA and FP at end-of-treatment. Conclusions: Despite differing molecular potencies, FP and TAA demonstrated comparable efficacy in the treatment of SAR, and produced similar occurrences of specific treatment-related side effects and similar improvements in overall patient HRQL. Ann Allergy Asthma Immunol 2002;89:56– 62.
INTRODUCTION Intranasal corticosteroids (INS) have been well established as the most effective class of medication in the treatment of seasonal and perennial allergic rhinitis (AR) symptoms.1 In the past, efficacy comparisons involving the use of INS have been based mainly on the in vitro potencies of the active corticosteroid molecules. Topical anti-inflammatory potency is routinely evaluated by the McKenzie skinblanching test, which has demonstrated fluticasone propionate (FP) to be the most molecularly potent of the INS, followed in rank order by mometasone furoate, budesonide, beclomethasone dipropionate, and triamcinolone acetonide (TAA).2 In addition, binding affinities and binding half-lives of human lung-corticosteroid receptors are commonly corre-
* Dallas Allergy & Asthma Center, Dallas, Texas. † Biogenics Research Institute, San Antonio, Texas. ‡ Aventis Pharmaceuticals, Bridgewater, New Jersey. § Formerly of Rhoˆne-Poulenc Rorer Pharmaceuticals, Collegeville, Pennsylvania. This work was supported by Aventis Pharmaceuticals. Received for publication August 22, 2001. Accepted for publication in revised form January 29, 2002.
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lated with the anti-inflammatory potency of intranasal or inhaled corticosteroids.3,4 The extremely long receptor-residency half-life of FP (11.5 hours) indicates higher molecular potency compared with TAA (3.9 hours) and other compounds measured5; T-cell cytokine inhibition measurements (taken from donor human peripheral blood samples) of FP have significantly surpassed those of other topical glucocorticoids tested, including TAA, budesonide, and beclomethasone dipropionate.6 The clinical relevance of these comparative in vitro measurements as indicators of efficacy is questionable. There is some concern as to whether the static nature of in vitro environments can accurately predict efficacy in the more dynamic disease state (AR) and in real-time clinical practice.7 We believe that head-to-head clinical comparisons are essential to better understanding the relationship between molecular potency and clinical efficacy, and therefore to better evaluating appropriate treatment options for patients requiring INS. AR has been demonstrated to have a significant detrimental effect on patient health-related quality of life (HRQL), a humanistic outcome that can be used to define objectively the limitations imposed by various diseases on the real-world
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well-being of patients.8 Accurate evaluation of the impact of treatment interventions will ultimately benefit both providers and patients by improving the overall quality of healthcare.9 Increasingly, HRQL is becoming more and more important a factor in the analysis of costs (eg, loss of productivity at work) associated with different AR treatments.10 These factors have made the use of sensitive disease-specific HRQL instruments common in clinical trials as well as in routine practice.11 Efficacy and HRQL should be considered in the selection of appropriate treatment for AR. Effective treatment should lead to reduced physician visits, enhanced HRQL, and increased patient satisfaction. These outcomes do not necessarily correlate with the molecular potency measurements of specific treatments. The primary objective of the present study was to compare the efficacy of TAA aqueous nasal spray (Nasacort AQ, Aventis Pharmaceuticals, Bridgewater, NJ) 220 g daily versus FP (Flonase, GlaxoSmithKline, Research Triangle Park, NC) 200 g daily in patients with fall seasonal AR. This study also compared the two treatment regimens with regard to safety profile, specific treatment-related side effects, and HRQL outcomes. METHODS Patient Population Male and female patients aged 12 to 70 years with at least a 2-year history of fall (ragweed) AR were eligible for inclusion upon confirmation (through skin prick testing) of allergic sensitivity to ragweed continuously present in the patient’s environment. A skin prick test was considered positive if the wheal and flare produced by the allergen was at least equal in size to that induced by the positive control (ie, histamine), or at least 5 mm larger than that induced by the negative control (ie, saline). Eligible patients were screened for significant abnormalities with physical exams, urinalysis, and hematology and serum chemistry tests. Female patients of childbearing potential were required to have been using an approved method of birth control for at least 2 months before the study, and to continue to do so throughout the course of the study. No pregnant or lactating patients were eligible for inclusion in the study. Also excluded were patients who had received any of the following within 42 days of the screening visit: an oral or parenteral short-acting steroid medication (excluding oral contraceptives and hormone replacement therapies such as estrogen), a long-acting steroid medication, a nasal corticosteroid/nasal cromolyn, or astemizole (Hismanal, Janssen, Titusville, NJ). Other patient exclusion criteria included: 1) history of abuse of nasal decongestants; 2) hypersensitivity or nonresponse to INSs; 3) initiation of immunotherapy within 1 month of study (although patients whose immunotherapy dose was being titrated were eligible, if their current dose could be maintained throughout the study period); 4) nasal pathology resulting in fixed occlusion of a nostril; 5) disease with the
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potential to interfere with the evaluation of study medications; 6) use of any medication that might independently affect the symptoms of seasonal AR; and 7) evidence of fungal infection in nose, mouth, or throat. Study Design This was an investigator-blind, randomized, parallel-group, active-controlled study conducted in eight centers in Texas during the 1996 fall season. All investigators agreed to comply with institutional review board Code of Federal Regulations and Informed Consent regulations (21 CFR 56 and 50). All patients provided written informed consent before participating in the study. Visit 1: Screening Patients were screened by medical history, skin prick test, physical examination, routine laboratory measurements, and pregnancy test (only for female subjects of childbearing potential) from 28 up to 5 days before randomization. During the 5-day baseline period before randomization, patients discontinued usage of all rhinitis medications, and completed daily symptom diary cards. The presence of elevated pollen counts in the vicinity of each investigational site during the baseline period was confirmed. Visit 2: Enrollment Before randomization, all eligible patients completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and submitted symptom diary cards to provide baseline symptom scores. Total nasal symptom (ie, discharge, stuffiness, itching, and sneezing) scores (TNSSs) from the morning of the randomization visit plus any 3 of the 4 previous days were required to exceed 42 (of a possible 84) points for all eligible patients. Eligible patients were randomized to receive TAA 220 g daily or FP 200 g daily as two sprays/nostril once daily in the morning for 3 weeks, and instructed to record 12-hour reflective symptom evaluations in the morning and evening. Study medications were delivered via metered-dose pump spray canisters with investigational labels lacking reference to specific product names or manufacturer’s identity. To maintain the investigator-blinding, each center was required to have a third-party individual who dispensed and collected the medications and instructed the patient on the proper use of nasal spray devices. The third party was also responsible for verifying patient compliance by review of diary cards when the medication was returned. The first dose of medication was administered under supervision at the study site to ensure proper use of the inhalation device. Symptom diary cards, medical resource utilization forms, and daily specific treatment-related side effects questionnaires were distributed to all patients. The investigator and other site personnel were required to remain blinded to the study medication. Visit 3: Final At the end of the 3-week study period, patients returned to the study center to complete the RQLQ for a second time, and to
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receive a final physical examination and exit interview. At this time, all symptom diary cards, medical resource utilization forms, and daily specific treatment-related side effects questionnaires were collected and examined for completeness. Patient compliance was evaluated through third-party evaluation of diary cards. Efficacy Evaluations Twelve-hour reflective symptom assessments were performed by patients upon arising (before dosing) in the morning (AM) and before going to bed in the evening (PM) over the course of the 3-week dosing period. Symptoms included: nasal discharge (anterior and/or posterior drainage), nasal stuffiness, nasal itching, sneezing, and ocular itching/tearing/ redness. Individual symptom severity was evaluated on a scale ranging from 0 to 3 (0 ⫽ absent; 1 ⫽ mild, present but not annoying; 2 ⫽ moderate, present and annoying, but does not interfere with sleep or daily living; 3 ⫽ severe, interferes with/or unable to carry out activities of daily living or sleep). Safety Evaluations Safety was evaluated using clinical examinations, laboratory tests, and adverse event reporting. Additionally, during the treatment period, daily questionnaires were used to collect patient evaluations of specific treatment-related side effects: 1) medication ran down throat; 2) medication ran out nose; 3) medication tasted bad; 4) medication smelled bad; 5) medication caused sneezing; 6) medication made nose sting/burn; 7) nose bleed; and 8) blood in mucus. Severity of these symptoms was rated on a 5-point scale (0 ⫽ not bothersome; 1 ⫽ slightly bothersome; 2 ⫽ moderately bothersome; 3 ⫽ quite bothersome; 4 ⫽ extremely bothersome). Quality of Life Evaluation The RQLQ was used at visits 2 and 3 to evaluate diseasespecific quality of life in all patients according to seven dimensions: activities, emotions, eye symptoms, nasal symptoms, non-hay fever problems, practical problems, and sleep. Overall quality of life was also evaluated by combining all dimension scores in a nonweighted manner. Individual dimension scores were derived from the mean scores of individual items within each dimension; overall HRQL scores were derived from the mean of all individual item scores regardless of dimension. Both mean dimension scores and overall HRQL scores were calculated using the RQLQ 7-point Likert scale (0 to 6; lower scores reflect better HRQL). Statistical Analysis To achieve a 90% power to detect a treatment difference of 0.2 in the mean change from baseline for TNSS, assuming a standard error of 0.5, 130 patients per treatment group were needed. The primary efficacy parameter was the mean total nasal symptom score (calculated as the sum of all individual nasal symptom scores) for TAA versus FP. Secondary efficacy parameters included the mean score for each individual nasal symptom, the mean score for ocular symptoms, and the patient dropout rate attributable to insufficient therapeutic effect.
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Treatment effect was evaluated using a two-sided test with a significance level 0.05 unless stated otherwise. For each symptom variable and each patient, a mean score was calculated for each week, the 3-week treatment period, and the 4-day baseline period. These variables were analyzed using an analysis of covariance (ANCOVA) with the mean change from baseline as the dependent variable, treatment and investigator as factors, and important baseline variables as covariates. The 2/Cochran-Mantel-Haenszel test was used to analyze the patient dropout rate for insufficient therapeutic effect. Safety parameters included occurrence of adverse events and specific treatment-related side effects. The overall proportions of patients with adverse events were compared between treatment groups using the 2/Fisher exact test. For each patient, the mean total score and mean individual scores for specific treatment-related side effects, recorded on the daily questionnaire, were calculated for each week and overall for the 3-week treatment period. These variables were analyzed using the ANCOVA with treatment and investigator as factors, and important baseline variables as covariates. The primary analysis of the HRQL data was the detection of differences in HRQL between the two treatment groups at visit 3, controlling for any existing differences in HRQL between the two groups at visit 2. This was evaluated by ANCOVA, with Table 1. Patient Demographics at Baseline: All Treated Patients Treatment group Characteristic
Age (years)* Mean ⫾ SD Median Range ⬍40 40–65 ⬎65 Gender Male Female Race Caucasian Black Oriental Hispanic Other Mean baseline symptom scores (SE) TNSS Nasal stuffiness Nasal discharge Nasal itch Sneezing Ocular symptoms
TAA (n ⴝ 172)
FP (n ⴝ 180)
n (%)
n (%)
40.0 ⫾ 12.2 40.0 12–69 83 (48.3) 85 (49.4) 4 (2.3)
37.5 ⫾ 12.4 37.0 12–66 101 (56.1) 78 (43.3) 1 (0.6)
57 (33.1) 115 (66.9)
61 (33.9) 119 (66.1)
142 (82.6) 6 (3.5) 1 (0.6) 20 (11.6) 3 (1.7)
144 (80.0) 9 (5.0) 2 (1.1) 25 (13.9) 0
8.95 (0.13) 2.41 (0.03) 2.35 (0.04) 2.17 (0.05) 2.02 (0.05) 2.02 (0.05)
9.01 (0.13) 2.45 (0.03) 2.35 (0.04) 2.24 (0.05) 1.96 (0.05) 2.06 (0.05)
* The difference in age between groups was statistically significant (P ⬍ 0.05).
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Figure 2. Reductions from baseline in mean individual symptom scores at endpoint: all treated patients. Figure 1. Percent reduction from baseline in mean daily TNSS each week and overall: all treated patients.
visit 2 RQLQ scores serving as covariates in the model. Statistical analysis for HRQL data was conducted using the Statistical Package for the Social Sciences (SPSS for Windows, Release 6.0, Chicago, IL). Statistical tests were reported at the ␣ ⫽ 0.05 level; HRQL comparisons between treatment groups were reported with 95% confidence intervals. HRQL analyses were conducted on evaluable subjects, ie, those who had quality of life measurements for both visits. Missing data for individual items were accommodated. Dimension (composed of more than three items) scores were analyzed. In cases where ⱖ50% of items were answered, dimension means were calculated. RESULTS Patient Disposition Three hundred fifty-two patients were enrolled into the two treatment groups (172 in the TAA group and 180 in the FP group), which were comparable for all baseline symptom scores, medical histories, laboratory results, and demographic
variables except age (40.0 ⫾ 12.2 years in the TAA group vs 37.5 ⫾ 12.4 years in the FP group; P ⬍ 0.05; Table 1). A total of 342 patients (97.2%) completed the entire 3-week treatment period, with 167 (97.1%) and 175 (97.2%) from the TAA and FP groups, respectively. Three TAA and 4 FP patients were discontinued because of major protocol violations, 2 TAA patients discontinued because of adverse events, and 1 FP patient discontinued because of “other” reasons. No patients withdrew from the study because of insufficient therapeutic effect. Efficacy Results There were no significant differences between TAA and FP in the mean change from baseline for daily TNSS, either overall (49.4% and 52.7%, respectively; P ⫽ 0.3323) or at any weekly timepoint in the treatment phase, regardless of pollen count. Reductions in mean TNSS for both treatment groups weekly and overall appear in Figure 1. There were no significant differences between TAA and FP in any individual symptom score (including ocular symptoms) at any time period except week 2, at which point FP provided a greater reduction than TAA in mean sneezing score (P ⫽ 0.046).
Table 2. Most Common (ⱖ5%) Possibly or Probably Related* Adverse Events TAA (n ⴝ 172)
Body system/event
Total number of patients with an adverse event Body as a whole Headache Digestive system Dyspepsia Musculoskeletal system Respiratory system Pharyngitis Rhinitis† Skin and appendages Application site reaction‡
FP (n ⴝ 180)
n (%) of patients
Possibly related
Probably related
n (%) of patients
Possibly related
Probably related
138 (80.2) 36 (20.9) 19 (11.0) 12 (7.0) 2 (1.2) 2 (1.2) 26 (15.1) 4 (2.3) 12 (7.0) 117 (68.0) 117 (68.0)
38 2 2 1 0 0 6 1 4 35 36
83 0 0 1 0 0 4 0 3 82 81
152 (84.4) 47 (26.1) 21 (11.7) 19 (10.6) 10 (5.6) 12 (6.7) 31 (17.2) 12 (6.7) 9 (5.0) 134 (74.4) 134 (74.4)
35 3 2 1 1 0 7 2 2 32 32
103 2 2 1 0 0 5 0 3 102 102
* For each event, patient was classified only once in the most probable category. † Cold, cold symptoms, common cold, common head cold, head cold, increased nasal dryness, infectious rhinitis, and nasal congestion were all coded as rhinitis. ‡ Application-site reaction, from the questionnaire, consisted of postdose burning, stinging, or sneezing; or blood in mucus.
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Overall reductions in individual symptom scores appear in Figure 2. Treatment responses were consistent across all eight study sites. No investigator-by-treatment interaction was seen at any timepoint. Safety Results Adverse events occurred in 138 TAA patients (80.2%) and 152 FP patients (84.4%), and were considered possibly or probably treatment-related in 121 and 138 cases, respectively. The most frequently occurring (ie, occurring in ⱖ5% of patients) treatment-related adverse events are summarized in Table 2. Two TAA patients withdrew because of adverse events (one patient because of nausea, the other because of nasal dryness, sinus dryness, and insomnia). Overall treatment-related side effect scores for patients taking FP were 2.97 and for those taking TAA 2.74; this difference was not statistically significant. Mean specific treatment-related side effect scores ranged from 0 to 1 (ie, not bothersome to moderately bothersome) for both treatment groups. TAA patients reported higher scores for “medication running out the nose” (P ⱕ 0.0478, overall and at weeks 1 and 2) and sneezing (P ⱕ 0.0365, overall and at weeks 1 and 2) than patients treated with FP. FP patients reported significantly higher scores for “medication smelled bad” at all time points (P ⱕ 0.0001), and complained of burning and stinging at week 3 (P ⫽ 0.0297). Specific treatment-related side effect scores are presented in Table 3. There were no clinically relevant differences between treatment groups in vital signs, physical examinations, or laboratory test results. Quality of Life Three hundred forty-nine patients were included in the HRQL analysis (170 and 179 randomized to TAA and FP, respectively). Treatment groups were similar, except with regard to mean age (TAA, 40.01 ⫾ 12.31; FP, 37.79 ⫾ 12.33; P ⫽ 0.470). Baseline RQLQ scores ranged from 3 to 4.5 (ie, moderately troubled to very troubled) for both treatment groups, compared with end-of-study scores ranging from 1 to 2 (ie, hardly troubled to somewhat troubled). There were no significant differences between TAA and FP in mean overall HRQL scores (P ⫽ 0.4) or in any individual RQLQ dimension except emotions, in which FP demonstrated statistically greater improvement than TAA (⫺2.16 and ⫺1.9, respectively; P ⫽ 0.04). Figure 3 illustrates the baseline and end-of-treatment RQLQ domain scores for each treatment group. DISCUSSION The demonstration of similar efficacy and safety of single daily doses of TAA compared with FP in the present study reinforces the need to distinguish molecular potency from clinical efficacy, and provides evidence that higher molecular potency does not necessarily translate into superior clinical efficacy. Very few studies have directly compared the efficacy of aqueous INS in the treatment of seasonal AR. One head-to-
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Table 3. Mean Specific Treatment-Related Side Effect Scores Week Parameter/treatment group Total side effect score TAA FP Medication ran down throat TAA FP Medication ran out nose TAA FP Medication tasted bad TAA FP Medication smelled bad TAA FP Medication caused sneezing TAA FP Medication made nose sting/burn TAA FP Nose bleed TAA FP Blood in mucus TAA FP
Overall* 1†
2‡
3§
3.02 3.04
2.69 2.99
2.44 2.81
2.74 2.97
0.85 0.75
0.82 0.80
0.77 0.73
0.82 0.76
0.96¶ 0.84¶ 0.75 0.74 0.64 0.62
0.85¶ 0.66
0.34 0.43
0.33 0.46
0.31 0.42
0.33 0.44
0.13 0.43㛳
0.11 0.41㛳
0.09 0.38㛳
0.12 0.42㛳
0.28¶ 0.23¶ 0.18 0.16 0.13 0.12
0.23¶ 0.14
0.42 0.46
0.33 0.44
0.28 0.43**
0.34 0.45
0.01 0.03
0.01 0.03
0.01 0.02
0.01 0.03
0.03 0.04
0.03 0.07
0.04 0.08
0.03 0.06
* TAA, n ⫽ 172; FP, n ⫽ 180 † TAA, n ⫽ 172; FP, n ⫽ 179 ‡ TAA, n ⫽ 170; FP, n ⫽ 177 § TAA, n ⫽ 170; FP, n ⫽ 179 ¶ P ⬍ 0.05; occurred with significantly greater frequency in TAA group than in FP group. 㛳 P ⬍ 0.0001; occurred with significantly greater frequency in FP group than in TAA group. ** P ⬍ 0.05; occurred with significantly greater frequency in FP group than in TAA group.
head study conducted in perennial AR patients demonstrated similar efficacy between FP and mimetasone furoate (MF) compared with placebo.12 FP and MF produced similar reductions from baseline in total nasal symptom scores (ie, discharge, congestion, itching, and sneezing) over the first 2 weeks of treatment (⫺39 and ⫺37%, respectively). The present study followed a different overall design, but demonstrated comparable results with both TAA and FP after 3 weeks of treatment based on a similar four-point symptom severity scale. These results also support those of a previous study comparing FP with an aerosol formulation of TAA, in which both products were demonstrated to be equally effective, safe, and well tolerated for the treatment of spring AR.13 In practice, however, the use of aqueous INS formulations is far more common than that of aerosol; the results of the present study,
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Figure 3. RQLQ scores at baseline (shown as dashed lines) and at end of treatment. *P ⬍ 0.05
therefore, are more broadly applicable to clinical practice. This study was designed to mimic real-life scenarios. For example, both drugs were administered at the recommended starting dosage, and to avoid nasal washout of actual medication by placebo treatment, no double dummy was used. Both TAA and FP have been demonstrated to be effective in the treatment of AR in previous placebo-controlled, doubleblind studies; because the present study examined comparative aspects of the two therapies, no placebo arm was used. Although the evaluation of patient preference was not the primary objective of this study, interesting data were observed in the treatment-related side effect profiles of TAA and FP. The higher occurrence of bad smell with FP than with TAA confirms recently presented data on patient preference with INS demonstrating patients’ ability to distinguish between INS based on the sensory attributes of individual sprays.14,15 Bachert et al,14 for example, demonstrated that patients significantly preferred TAA to both FP and MF for strength of odor and liking of odor immediately after administration (P ⱕ 0.001). It is worthwhile to mention that TAA is the only one of these products specifically formulated to be odorless, a claim that is supported by these findings as well as the findings of the present study. The higher occurrence of stinging and burning with FP at week 3 is unexplained, as is the higher occurrence of sneezing in the TAA group. Patients also reported more medication run-off associated with TAA than with FP. Although the present study was designed to identify only the occurrence (not the duration) of side effects, the results of another study comparing sensory attributes of TAA 55 g and FP 50 g indicate that medication run-off with both products subsided to comparable levels 2 minutes after application.14 Interestingly, epistaxis was not found in this study to be among the most common treatment-emergent adverse events in either group; this may be the result of the instructions provided at the clinic on the correct use of study medications. If so, it would confirm the clinical value of day-to-day patient instruction on the proper use of metered-dose pump sprays.
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Although this study supports a comparable adverse event profile for TAA and FP, studies designed to evaluate the effect of INS on hypothalamic-pituitary-adrenal axis function suggest that high molecular potency may be associated with potentially undesirable consequences because of the wide presence and distribution of glucocorticoid receptors throughout various body systems.7 In practice, patients with mild or moderate disease often receive dosages of INS equivalent to those prescribed in more severe cases. The risks in this situation, albeit small, may outweigh the benefits,7 especially considering that, in this study, high molecular potency does not seem to correlate with superior clinical effectiveness. As a rule, INS should be used at the lowest fully effective dose once symptom control is achieved. More attention is being given to patient HRQL as an issue to consider in determining appropriate treatment for AR; validated instruments are now available to evaluate accurately the impact of AR on HRQL and should be included as a standard measurement in AR clinical trials.9 In the present study, the RQLQ was selected to compare the two treatment groups with regard to HRQL because it has been proven a reliable, disease-specific indicator of the impact of AR on issues affecting patient well-being.16 Both TAA and FP significantly and similarly improved the overall RQLQ score after 3 weeks of treatment. Further, no difference was observed between the two treatments in 6 of 7 domains of the RQLQ. A statistically significant greater improvement in the emotions domain was observed with FP versus TAA; however, this was an isolated finding and did not reach the level associated with clinical relevance. Despite differing molecular potencies, TAA and FP were found in parallel comparison to exhibit comparable improvement in TNSS in patients with seasonal AR when administered at recommended dosages for 3 weeks. No significant differences were observed between treatment groups in improvement in overall HRQL score, and both treatments were equally safe and well tolerated.
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REFERENCES 1. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. 2000;3:51–58. www.theallergyreport.org. 2. Johnson M. Development of fluticasone propionate and comparison with other inhaled corticosteroids. J Allergy Clin Immunol 1998;101:S434 –S439. 3. National Asthma Education and Prevention Program. Expert Panel Report II. Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health Publication, May 1997. 4. Smith CL, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Arzneimittelforschung 1998;48:956 –960. 5. Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994;59: 597– 602. 6. Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-␥ production by cultured primary CD4⫹ T cells. J Allergy Clin Immunol 1997;100:511–519. 7. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids. Drug Saf 2000;23:11–33. 8. Bousquet J, Bullinger M, Fayol C, et al. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 health status questionnaire. J Allergy Clin Immunol 1994;94:182–188. 9. Tanner LA, Reilly M, Meltzer EO, et al. Effect of fexofenadine HCl on quality of life and work, classroom, and daily activity impairment in patients with seasonal allergic rhinitis. Am J Manag Care 1999;5(Suppl):S235–S247.
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10. Blaiss MS. Quality of life in allergic rhinitis. Ann Allergy Asthma Immunol 1999;83:449 – 454. 11. Juniper EF. Measuring health-related quality of life in rhinitis. J Allergy Clin Immunol 1997;99:S742—S749. 12. Mandl M, Nolop K, Lutsky BN. Comparison of once daily mometasone furoate (Nasonex) and fluticasone propionate aqueous nasal sprays for the treatment of perennial rhinitis. 194 – 079 Study Group. Ann Allergy Asthma Immunol 1997; 79:370 –378. 13. Small P, Houle P, Day JH, et al. A comparison of triamcinolone acetonide nasal aerosol spray and fluticasone propionate aqueous solution spray in the treatment of spring allergic rhinitis. J Allergy Clin Immunol 1997;100:592–595. 14. Bachert C, El-Akkad T. Patient preferences and sensory comparisons of three intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. In press. 15. Gerson I, Green L, Fishken D. Patient preference and sensory comparisons of nasal spray allergy medications. J Sensory Stud 1999;14:491– 496. 16. Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials. J Allergy Clin Immunol 1994;93:413– 421. Requests for reprints should be addressed to: George C. Georges, MD Aventis Pharmaceuticals, 300 Somerset Corporate Boulevard, SC3–320B Bridgewater, NJ 08807-2854 E-mail: [email protected]
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Background: The topical potency of fluticasone propionate (FP) is known to be four times greater than that of triamcinolone acetonide (TAA). However, the significance of this difference has not been proven in the clinical treatment of seasonal allergic rhinitis (SAR). Objective: To compare the efficacy, safety, and effect on health-related quality of life (HRQL) of FP and TAA aqueous nasal sprays in patients with SAR Methods: Single-blind, parallel-group, active-controlled design. Patients were randomized to 3-week treatment with TAA 220 g (n ⫽ 172) or FP 200 g (n ⫽ 180) as two sprays/nostril once daily AM. Twelve-hour reflective symptom evaluations (nasal discharge, stuffiness, itching; sneezing; ocular itching/tearing/redness) were performed AM/PM, beginning at pretreatment baseline period. Incidences of specific treatment-related side effects were collected in daily questionnaires. HRQL was evaluated at baseline and end-of-treatment with a validated disease-specific, quality-of-life instrument. Results: TAA and FP produced similar improvement in daily total nasal symptom scores overall (49.4% and 52.7%, respectively; P ⫽ 0.332) and at every weekly time point (P ⬎ 0.05). There were no significant differences between TAA and FP in any individual symptom score at any time point except week 2 (FP provided greater reduction in sneezing, P ⫽ 0.046). No significant difference was found between groups in overall occurrence of specific treatment-related side effects. Overall Rhinoconjunctivitis Quality of Life Questionnaire scores were similar for TAA and FP at end-of-treatment. Conclusions: Despite differing molecular potencies, FP and TAA demonstrated comparable efficacy in the treatment of SAR, and produced similar occurrences of specific treatment-related side effects and similar improvements in overall patient HRQL. Ann Allergy Asthma Immunol 2002;89:56– 62.
INTRODUCTION Intranasal corticosteroids (INS) have been well established as the most effective class of medication in the treatment of seasonal and perennial allergic rhinitis (AR) symptoms.1 In the past, efficacy comparisons involving the use of INS have been based mainly on the in vitro potencies of the active corticosteroid molecules. Topical anti-inflammatory potency is routinely evaluated by the McKenzie skinblanching test, which has demonstrated fluticasone propionate (FP) to be the most molecularly potent of the INS, followed in rank order by mometasone furoate, budesonide, beclomethasone dipropionate, and triamcinolone acetonide (TAA).2 In addition, binding affinities and binding half-lives of human lung-corticosteroid receptors are commonly corre-
* Dallas Allergy & Asthma Center, Dallas, Texas. † Biogenics Research Institute, San Antonio, Texas. ‡ Aventis Pharmaceuticals, Bridgewater, New Jersey. § Formerly of Rhoˆne-Poulenc Rorer Pharmaceuticals, Collegeville, Pennsylvania. This work was supported by Aventis Pharmaceuticals. Received for publication August 22, 2001. Accepted for publication in revised form January 29, 2002.
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lated with the anti-inflammatory potency of intranasal or inhaled corticosteroids.3,4 The extremely long receptor-residency half-life of FP (11.5 hours) indicates higher molecular potency compared with TAA (3.9 hours) and other compounds measured5; T-cell cytokine inhibition measurements (taken from donor human peripheral blood samples) of FP have significantly surpassed those of other topical glucocorticoids tested, including TAA, budesonide, and beclomethasone dipropionate.6 The clinical relevance of these comparative in vitro measurements as indicators of efficacy is questionable. There is some concern as to whether the static nature of in vitro environments can accurately predict efficacy in the more dynamic disease state (AR) and in real-time clinical practice.7 We believe that head-to-head clinical comparisons are essential to better understanding the relationship between molecular potency and clinical efficacy, and therefore to better evaluating appropriate treatment options for patients requiring INS. AR has been demonstrated to have a significant detrimental effect on patient health-related quality of life (HRQL), a humanistic outcome that can be used to define objectively the limitations imposed by various diseases on the real-world
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well-being of patients.8 Accurate evaluation of the impact of treatment interventions will ultimately benefit both providers and patients by improving the overall quality of healthcare.9 Increasingly, HRQL is becoming more and more important a factor in the analysis of costs (eg, loss of productivity at work) associated with different AR treatments.10 These factors have made the use of sensitive disease-specific HRQL instruments common in clinical trials as well as in routine practice.11 Efficacy and HRQL should be considered in the selection of appropriate treatment for AR. Effective treatment should lead to reduced physician visits, enhanced HRQL, and increased patient satisfaction. These outcomes do not necessarily correlate with the molecular potency measurements of specific treatments. The primary objective of the present study was to compare the efficacy of TAA aqueous nasal spray (Nasacort AQ, Aventis Pharmaceuticals, Bridgewater, NJ) 220 g daily versus FP (Flonase, GlaxoSmithKline, Research Triangle Park, NC) 200 g daily in patients with fall seasonal AR. This study also compared the two treatment regimens with regard to safety profile, specific treatment-related side effects, and HRQL outcomes. METHODS Patient Population Male and female patients aged 12 to 70 years with at least a 2-year history of fall (ragweed) AR were eligible for inclusion upon confirmation (through skin prick testing) of allergic sensitivity to ragweed continuously present in the patient’s environment. A skin prick test was considered positive if the wheal and flare produced by the allergen was at least equal in size to that induced by the positive control (ie, histamine), or at least 5 mm larger than that induced by the negative control (ie, saline). Eligible patients were screened for significant abnormalities with physical exams, urinalysis, and hematology and serum chemistry tests. Female patients of childbearing potential were required to have been using an approved method of birth control for at least 2 months before the study, and to continue to do so throughout the course of the study. No pregnant or lactating patients were eligible for inclusion in the study. Also excluded were patients who had received any of the following within 42 days of the screening visit: an oral or parenteral short-acting steroid medication (excluding oral contraceptives and hormone replacement therapies such as estrogen), a long-acting steroid medication, a nasal corticosteroid/nasal cromolyn, or astemizole (Hismanal, Janssen, Titusville, NJ). Other patient exclusion criteria included: 1) history of abuse of nasal decongestants; 2) hypersensitivity or nonresponse to INSs; 3) initiation of immunotherapy within 1 month of study (although patients whose immunotherapy dose was being titrated were eligible, if their current dose could be maintained throughout the study period); 4) nasal pathology resulting in fixed occlusion of a nostril; 5) disease with the
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potential to interfere with the evaluation of study medications; 6) use of any medication that might independently affect the symptoms of seasonal AR; and 7) evidence of fungal infection in nose, mouth, or throat. Study Design This was an investigator-blind, randomized, parallel-group, active-controlled study conducted in eight centers in Texas during the 1996 fall season. All investigators agreed to comply with institutional review board Code of Federal Regulations and Informed Consent regulations (21 CFR 56 and 50). All patients provided written informed consent before participating in the study. Visit 1: Screening Patients were screened by medical history, skin prick test, physical examination, routine laboratory measurements, and pregnancy test (only for female subjects of childbearing potential) from 28 up to 5 days before randomization. During the 5-day baseline period before randomization, patients discontinued usage of all rhinitis medications, and completed daily symptom diary cards. The presence of elevated pollen counts in the vicinity of each investigational site during the baseline period was confirmed. Visit 2: Enrollment Before randomization, all eligible patients completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and submitted symptom diary cards to provide baseline symptom scores. Total nasal symptom (ie, discharge, stuffiness, itching, and sneezing) scores (TNSSs) from the morning of the randomization visit plus any 3 of the 4 previous days were required to exceed 42 (of a possible 84) points for all eligible patients. Eligible patients were randomized to receive TAA 220 g daily or FP 200 g daily as two sprays/nostril once daily in the morning for 3 weeks, and instructed to record 12-hour reflective symptom evaluations in the morning and evening. Study medications were delivered via metered-dose pump spray canisters with investigational labels lacking reference to specific product names or manufacturer’s identity. To maintain the investigator-blinding, each center was required to have a third-party individual who dispensed and collected the medications and instructed the patient on the proper use of nasal spray devices. The third party was also responsible for verifying patient compliance by review of diary cards when the medication was returned. The first dose of medication was administered under supervision at the study site to ensure proper use of the inhalation device. Symptom diary cards, medical resource utilization forms, and daily specific treatment-related side effects questionnaires were distributed to all patients. The investigator and other site personnel were required to remain blinded to the study medication. Visit 3: Final At the end of the 3-week study period, patients returned to the study center to complete the RQLQ for a second time, and to
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receive a final physical examination and exit interview. At this time, all symptom diary cards, medical resource utilization forms, and daily specific treatment-related side effects questionnaires were collected and examined for completeness. Patient compliance was evaluated through third-party evaluation of diary cards. Efficacy Evaluations Twelve-hour reflective symptom assessments were performed by patients upon arising (before dosing) in the morning (AM) and before going to bed in the evening (PM) over the course of the 3-week dosing period. Symptoms included: nasal discharge (anterior and/or posterior drainage), nasal stuffiness, nasal itching, sneezing, and ocular itching/tearing/ redness. Individual symptom severity was evaluated on a scale ranging from 0 to 3 (0 ⫽ absent; 1 ⫽ mild, present but not annoying; 2 ⫽ moderate, present and annoying, but does not interfere with sleep or daily living; 3 ⫽ severe, interferes with/or unable to carry out activities of daily living or sleep). Safety Evaluations Safety was evaluated using clinical examinations, laboratory tests, and adverse event reporting. Additionally, during the treatment period, daily questionnaires were used to collect patient evaluations of specific treatment-related side effects: 1) medication ran down throat; 2) medication ran out nose; 3) medication tasted bad; 4) medication smelled bad; 5) medication caused sneezing; 6) medication made nose sting/burn; 7) nose bleed; and 8) blood in mucus. Severity of these symptoms was rated on a 5-point scale (0 ⫽ not bothersome; 1 ⫽ slightly bothersome; 2 ⫽ moderately bothersome; 3 ⫽ quite bothersome; 4 ⫽ extremely bothersome). Quality of Life Evaluation The RQLQ was used at visits 2 and 3 to evaluate diseasespecific quality of life in all patients according to seven dimensions: activities, emotions, eye symptoms, nasal symptoms, non-hay fever problems, practical problems, and sleep. Overall quality of life was also evaluated by combining all dimension scores in a nonweighted manner. Individual dimension scores were derived from the mean scores of individual items within each dimension; overall HRQL scores were derived from the mean of all individual item scores regardless of dimension. Both mean dimension scores and overall HRQL scores were calculated using the RQLQ 7-point Likert scale (0 to 6; lower scores reflect better HRQL). Statistical Analysis To achieve a 90% power to detect a treatment difference of 0.2 in the mean change from baseline for TNSS, assuming a standard error of 0.5, 130 patients per treatment group were needed. The primary efficacy parameter was the mean total nasal symptom score (calculated as the sum of all individual nasal symptom scores) for TAA versus FP. Secondary efficacy parameters included the mean score for each individual nasal symptom, the mean score for ocular symptoms, and the patient dropout rate attributable to insufficient therapeutic effect.
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Treatment effect was evaluated using a two-sided test with a significance level 0.05 unless stated otherwise. For each symptom variable and each patient, a mean score was calculated for each week, the 3-week treatment period, and the 4-day baseline period. These variables were analyzed using an analysis of covariance (ANCOVA) with the mean change from baseline as the dependent variable, treatment and investigator as factors, and important baseline variables as covariates. The 2/Cochran-Mantel-Haenszel test was used to analyze the patient dropout rate for insufficient therapeutic effect. Safety parameters included occurrence of adverse events and specific treatment-related side effects. The overall proportions of patients with adverse events were compared between treatment groups using the 2/Fisher exact test. For each patient, the mean total score and mean individual scores for specific treatment-related side effects, recorded on the daily questionnaire, were calculated for each week and overall for the 3-week treatment period. These variables were analyzed using the ANCOVA with treatment and investigator as factors, and important baseline variables as covariates. The primary analysis of the HRQL data was the detection of differences in HRQL between the two treatment groups at visit 3, controlling for any existing differences in HRQL between the two groups at visit 2. This was evaluated by ANCOVA, with Table 1. Patient Demographics at Baseline: All Treated Patients Treatment group Characteristic
Age (years)* Mean ⫾ SD Median Range ⬍40 40–65 ⬎65 Gender Male Female Race Caucasian Black Oriental Hispanic Other Mean baseline symptom scores (SE) TNSS Nasal stuffiness Nasal discharge Nasal itch Sneezing Ocular symptoms
TAA (n ⴝ 172)
FP (n ⴝ 180)
n (%)
n (%)
40.0 ⫾ 12.2 40.0 12–69 83 (48.3) 85 (49.4) 4 (2.3)
37.5 ⫾ 12.4 37.0 12–66 101 (56.1) 78 (43.3) 1 (0.6)
57 (33.1) 115 (66.9)
61 (33.9) 119 (66.1)
142 (82.6) 6 (3.5) 1 (0.6) 20 (11.6) 3 (1.7)
144 (80.0) 9 (5.0) 2 (1.1) 25 (13.9) 0
8.95 (0.13) 2.41 (0.03) 2.35 (0.04) 2.17 (0.05) 2.02 (0.05) 2.02 (0.05)
9.01 (0.13) 2.45 (0.03) 2.35 (0.04) 2.24 (0.05) 1.96 (0.05) 2.06 (0.05)
* The difference in age between groups was statistically significant (P ⬍ 0.05).
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Figure 2. Reductions from baseline in mean individual symptom scores at endpoint: all treated patients. Figure 1. Percent reduction from baseline in mean daily TNSS each week and overall: all treated patients.
visit 2 RQLQ scores serving as covariates in the model. Statistical analysis for HRQL data was conducted using the Statistical Package for the Social Sciences (SPSS for Windows, Release 6.0, Chicago, IL). Statistical tests were reported at the ␣ ⫽ 0.05 level; HRQL comparisons between treatment groups were reported with 95% confidence intervals. HRQL analyses were conducted on evaluable subjects, ie, those who had quality of life measurements for both visits. Missing data for individual items were accommodated. Dimension (composed of more than three items) scores were analyzed. In cases where ⱖ50% of items were answered, dimension means were calculated. RESULTS Patient Disposition Three hundred fifty-two patients were enrolled into the two treatment groups (172 in the TAA group and 180 in the FP group), which were comparable for all baseline symptom scores, medical histories, laboratory results, and demographic
variables except age (40.0 ⫾ 12.2 years in the TAA group vs 37.5 ⫾ 12.4 years in the FP group; P ⬍ 0.05; Table 1). A total of 342 patients (97.2%) completed the entire 3-week treatment period, with 167 (97.1%) and 175 (97.2%) from the TAA and FP groups, respectively. Three TAA and 4 FP patients were discontinued because of major protocol violations, 2 TAA patients discontinued because of adverse events, and 1 FP patient discontinued because of “other” reasons. No patients withdrew from the study because of insufficient therapeutic effect. Efficacy Results There were no significant differences between TAA and FP in the mean change from baseline for daily TNSS, either overall (49.4% and 52.7%, respectively; P ⫽ 0.3323) or at any weekly timepoint in the treatment phase, regardless of pollen count. Reductions in mean TNSS for both treatment groups weekly and overall appear in Figure 1. There were no significant differences between TAA and FP in any individual symptom score (including ocular symptoms) at any time period except week 2, at which point FP provided a greater reduction than TAA in mean sneezing score (P ⫽ 0.046).
Table 2. Most Common (ⱖ5%) Possibly or Probably Related* Adverse Events TAA (n ⴝ 172)
Body system/event
Total number of patients with an adverse event Body as a whole Headache Digestive system Dyspepsia Musculoskeletal system Respiratory system Pharyngitis Rhinitis† Skin and appendages Application site reaction‡
FP (n ⴝ 180)
n (%) of patients
Possibly related
Probably related
n (%) of patients
Possibly related
Probably related
138 (80.2) 36 (20.9) 19 (11.0) 12 (7.0) 2 (1.2) 2 (1.2) 26 (15.1) 4 (2.3) 12 (7.0) 117 (68.0) 117 (68.0)
38 2 2 1 0 0 6 1 4 35 36
83 0 0 1 0 0 4 0 3 82 81
152 (84.4) 47 (26.1) 21 (11.7) 19 (10.6) 10 (5.6) 12 (6.7) 31 (17.2) 12 (6.7) 9 (5.0) 134 (74.4) 134 (74.4)
35 3 2 1 1 0 7 2 2 32 32
103 2 2 1 0 0 5 0 3 102 102
* For each event, patient was classified only once in the most probable category. † Cold, cold symptoms, common cold, common head cold, head cold, increased nasal dryness, infectious rhinitis, and nasal congestion were all coded as rhinitis. ‡ Application-site reaction, from the questionnaire, consisted of postdose burning, stinging, or sneezing; or blood in mucus.
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Overall reductions in individual symptom scores appear in Figure 2. Treatment responses were consistent across all eight study sites. No investigator-by-treatment interaction was seen at any timepoint. Safety Results Adverse events occurred in 138 TAA patients (80.2%) and 152 FP patients (84.4%), and were considered possibly or probably treatment-related in 121 and 138 cases, respectively. The most frequently occurring (ie, occurring in ⱖ5% of patients) treatment-related adverse events are summarized in Table 2. Two TAA patients withdrew because of adverse events (one patient because of nausea, the other because of nasal dryness, sinus dryness, and insomnia). Overall treatment-related side effect scores for patients taking FP were 2.97 and for those taking TAA 2.74; this difference was not statistically significant. Mean specific treatment-related side effect scores ranged from 0 to 1 (ie, not bothersome to moderately bothersome) for both treatment groups. TAA patients reported higher scores for “medication running out the nose” (P ⱕ 0.0478, overall and at weeks 1 and 2) and sneezing (P ⱕ 0.0365, overall and at weeks 1 and 2) than patients treated with FP. FP patients reported significantly higher scores for “medication smelled bad” at all time points (P ⱕ 0.0001), and complained of burning and stinging at week 3 (P ⫽ 0.0297). Specific treatment-related side effect scores are presented in Table 3. There were no clinically relevant differences between treatment groups in vital signs, physical examinations, or laboratory test results. Quality of Life Three hundred forty-nine patients were included in the HRQL analysis (170 and 179 randomized to TAA and FP, respectively). Treatment groups were similar, except with regard to mean age (TAA, 40.01 ⫾ 12.31; FP, 37.79 ⫾ 12.33; P ⫽ 0.470). Baseline RQLQ scores ranged from 3 to 4.5 (ie, moderately troubled to very troubled) for both treatment groups, compared with end-of-study scores ranging from 1 to 2 (ie, hardly troubled to somewhat troubled). There were no significant differences between TAA and FP in mean overall HRQL scores (P ⫽ 0.4) or in any individual RQLQ dimension except emotions, in which FP demonstrated statistically greater improvement than TAA (⫺2.16 and ⫺1.9, respectively; P ⫽ 0.04). Figure 3 illustrates the baseline and end-of-treatment RQLQ domain scores for each treatment group. DISCUSSION The demonstration of similar efficacy and safety of single daily doses of TAA compared with FP in the present study reinforces the need to distinguish molecular potency from clinical efficacy, and provides evidence that higher molecular potency does not necessarily translate into superior clinical efficacy. Very few studies have directly compared the efficacy of aqueous INS in the treatment of seasonal AR. One head-to-
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Table 3. Mean Specific Treatment-Related Side Effect Scores Week Parameter/treatment group Total side effect score TAA FP Medication ran down throat TAA FP Medication ran out nose TAA FP Medication tasted bad TAA FP Medication smelled bad TAA FP Medication caused sneezing TAA FP Medication made nose sting/burn TAA FP Nose bleed TAA FP Blood in mucus TAA FP
Overall* 1†
2‡
3§
3.02 3.04
2.69 2.99
2.44 2.81
2.74 2.97
0.85 0.75
0.82 0.80
0.77 0.73
0.82 0.76
0.96¶ 0.84¶ 0.75 0.74 0.64 0.62
0.85¶ 0.66
0.34 0.43
0.33 0.46
0.31 0.42
0.33 0.44
0.13 0.43㛳
0.11 0.41㛳
0.09 0.38㛳
0.12 0.42㛳
0.28¶ 0.23¶ 0.18 0.16 0.13 0.12
0.23¶ 0.14
0.42 0.46
0.33 0.44
0.28 0.43**
0.34 0.45
0.01 0.03
0.01 0.03
0.01 0.02
0.01 0.03
0.03 0.04
0.03 0.07
0.04 0.08
0.03 0.06
* TAA, n ⫽ 172; FP, n ⫽ 180 † TAA, n ⫽ 172; FP, n ⫽ 179 ‡ TAA, n ⫽ 170; FP, n ⫽ 177 § TAA, n ⫽ 170; FP, n ⫽ 179 ¶ P ⬍ 0.05; occurred with significantly greater frequency in TAA group than in FP group. 㛳 P ⬍ 0.0001; occurred with significantly greater frequency in FP group than in TAA group. ** P ⬍ 0.05; occurred with significantly greater frequency in FP group than in TAA group.
head study conducted in perennial AR patients demonstrated similar efficacy between FP and mimetasone furoate (MF) compared with placebo.12 FP and MF produced similar reductions from baseline in total nasal symptom scores (ie, discharge, congestion, itching, and sneezing) over the first 2 weeks of treatment (⫺39 and ⫺37%, respectively). The present study followed a different overall design, but demonstrated comparable results with both TAA and FP after 3 weeks of treatment based on a similar four-point symptom severity scale. These results also support those of a previous study comparing FP with an aerosol formulation of TAA, in which both products were demonstrated to be equally effective, safe, and well tolerated for the treatment of spring AR.13 In practice, however, the use of aqueous INS formulations is far more common than that of aerosol; the results of the present study,
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Figure 3. RQLQ scores at baseline (shown as dashed lines) and at end of treatment. *P ⬍ 0.05
therefore, are more broadly applicable to clinical practice. This study was designed to mimic real-life scenarios. For example, both drugs were administered at the recommended starting dosage, and to avoid nasal washout of actual medication by placebo treatment, no double dummy was used. Both TAA and FP have been demonstrated to be effective in the treatment of AR in previous placebo-controlled, doubleblind studies; because the present study examined comparative aspects of the two therapies, no placebo arm was used. Although the evaluation of patient preference was not the primary objective of this study, interesting data were observed in the treatment-related side effect profiles of TAA and FP. The higher occurrence of bad smell with FP than with TAA confirms recently presented data on patient preference with INS demonstrating patients’ ability to distinguish between INS based on the sensory attributes of individual sprays.14,15 Bachert et al,14 for example, demonstrated that patients significantly preferred TAA to both FP and MF for strength of odor and liking of odor immediately after administration (P ⱕ 0.001). It is worthwhile to mention that TAA is the only one of these products specifically formulated to be odorless, a claim that is supported by these findings as well as the findings of the present study. The higher occurrence of stinging and burning with FP at week 3 is unexplained, as is the higher occurrence of sneezing in the TAA group. Patients also reported more medication run-off associated with TAA than with FP. Although the present study was designed to identify only the occurrence (not the duration) of side effects, the results of another study comparing sensory attributes of TAA 55 g and FP 50 g indicate that medication run-off with both products subsided to comparable levels 2 minutes after application.14 Interestingly, epistaxis was not found in this study to be among the most common treatment-emergent adverse events in either group; this may be the result of the instructions provided at the clinic on the correct use of study medications. If so, it would confirm the clinical value of day-to-day patient instruction on the proper use of metered-dose pump sprays.
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Although this study supports a comparable adverse event profile for TAA and FP, studies designed to evaluate the effect of INS on hypothalamic-pituitary-adrenal axis function suggest that high molecular potency may be associated with potentially undesirable consequences because of the wide presence and distribution of glucocorticoid receptors throughout various body systems.7 In practice, patients with mild or moderate disease often receive dosages of INS equivalent to those prescribed in more severe cases. The risks in this situation, albeit small, may outweigh the benefits,7 especially considering that, in this study, high molecular potency does not seem to correlate with superior clinical effectiveness. As a rule, INS should be used at the lowest fully effective dose once symptom control is achieved. More attention is being given to patient HRQL as an issue to consider in determining appropriate treatment for AR; validated instruments are now available to evaluate accurately the impact of AR on HRQL and should be included as a standard measurement in AR clinical trials.9 In the present study, the RQLQ was selected to compare the two treatment groups with regard to HRQL because it has been proven a reliable, disease-specific indicator of the impact of AR on issues affecting patient well-being.16 Both TAA and FP significantly and similarly improved the overall RQLQ score after 3 weeks of treatment. Further, no difference was observed between the two treatments in 6 of 7 domains of the RQLQ. A statistically significant greater improvement in the emotions domain was observed with FP versus TAA; however, this was an isolated finding and did not reach the level associated with clinical relevance. Despite differing molecular potencies, TAA and FP were found in parallel comparison to exhibit comparable improvement in TNSS in patients with seasonal AR when administered at recommended dosages for 3 weeks. No significant differences were observed between treatment groups in improvement in overall HRQL score, and both treatments were equally safe and well tolerated.
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REFERENCES 1. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. 2000;3:51–58. www.theallergyreport.org. 2. Johnson M. Development of fluticasone propionate and comparison with other inhaled corticosteroids. J Allergy Clin Immunol 1998;101:S434 –S439. 3. National Asthma Education and Prevention Program. Expert Panel Report II. Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health Publication, May 1997. 4. Smith CL, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Arzneimittelforschung 1998;48:956 –960. 5. Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994;59: 597– 602. 6. Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-␥ production by cultured primary CD4⫹ T cells. J Allergy Clin Immunol 1997;100:511–519. 7. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids. Drug Saf 2000;23:11–33. 8. Bousquet J, Bullinger M, Fayol C, et al. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 health status questionnaire. J Allergy Clin Immunol 1994;94:182–188. 9. Tanner LA, Reilly M, Meltzer EO, et al. Effect of fexofenadine HCl on quality of life and work, classroom, and daily activity impairment in patients with seasonal allergic rhinitis. Am J Manag Care 1999;5(Suppl):S235–S247.
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10. Blaiss MS. Quality of life in allergic rhinitis. Ann Allergy Asthma Immunol 1999;83:449 – 454. 11. Juniper EF. Measuring health-related quality of life in rhinitis. J Allergy Clin Immunol 1997;99:S742—S749. 12. Mandl M, Nolop K, Lutsky BN. Comparison of once daily mometasone furoate (Nasonex) and fluticasone propionate aqueous nasal sprays for the treatment of perennial rhinitis. 194 – 079 Study Group. Ann Allergy Asthma Immunol 1997; 79:370 –378. 13. Small P, Houle P, Day JH, et al. A comparison of triamcinolone acetonide nasal aerosol spray and fluticasone propionate aqueous solution spray in the treatment of spring allergic rhinitis. J Allergy Clin Immunol 1997;100:592–595. 14. Bachert C, El-Akkad T. Patient preferences and sensory comparisons of three intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. In press. 15. Gerson I, Green L, Fishken D. Patient preference and sensory comparisons of nasal spray allergy medications. J Sensory Stud 1999;14:491– 496. 16. Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials. J Allergy Clin Immunol 1994;93:413– 421. Requests for reprints should be addressed to: George C. Georges, MD Aventis Pharmaceuticals, 300 Somerset Corporate Boulevard, SC3–320B Bridgewater, NJ 08807-2854 E-mail: [email protected]
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