- Email: [email protected]
Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis
Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis Anjuli S. Nayak, MD*; Guy A. Settipane, MD†; Andrew Pedinoff, MD‡; B. Lauren Charous, MD§; Eli O. Meltzer, MD¶; William W. Busse, MD储; S. James Zinreich, MD**; Richard R. Lorber, MD††; Ger Rikken, MD††; Melvyn R. Danzig, PhD††; and the Nasonex Sinusitis Group‡‡ Background: Mometasone furoate nasal spray (MFNS) 400 g, twice daily, as adjunctive treatment with oral antibiotic significantly improved symptoms of recurrent rhinosinusitis. Objective: To evaluate the effectiveness and safety of MFNS 200 g, twice daily, and 400 g, twice daily, compared with placebo as adjunctive treatment with oral antibiotic for acute rhinosinusitis. Methods: In this multicenter, double-blind, placebo-controlled study, 967 outpatients with computed tomographic scanconfirmed moderate to severe rhinosinusitis received amoxicillin/clavulanate potassium (Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, for 21 days with adjunctive twice daily MFNS 200 g, MFNS 400 g, or placebo nasal spray. Patients recorded scores of six rhinosinusitis symptoms and any adverse events twice daily. Pre- and postcosyntropin–stimulation plasma cortisol levels were measured in a subset of patients at selected study sites. Results: Treatment with MFNS 200 g or 400 g, twice daily, produced significantly greater improvements in total symptoms score (primary efficacy variable) day 1 to day 15 average (50% and 51%, respectively) than placebo (44%, P ⱕ 0.017). Both doses of MFNS produced significant total symptoms score improvement over placebo by day 4, and maintained efficacy over the entire 21-day study. Relief of individual symptoms showed a similar pattern. Both doses of MFNS were well tolerated, and adverse events were similar to that of placebo. Cosyntropin stimulation showed no evidence of hypothalamic-pituitary-adrenal axis suppression. Conclusions: As adjunctive therapy to oral antibiotic treatment, MFNS at doses of 200 g or 400 g, twice daily, was well tolerated and significantly more effective in reducing the symptoms of rhinosinusitis than antibiotic therapy alone. Ann Allergy Asthma Immunol 2002;89:271–278.
INTRODUCTION Rhinosinusitis is a common disease which can have a troublesome impact on daily life, affecting an estimated 35 million Americans annually, and causing a significant clinical and economic burden.1–3 Recent estimates place annual rhinosinusitis-related health care expenditures in excess of US$6 billion, with ⬎50% of that amount attributed to a primary diagnosis of acute or chronic rhinosinusitis.3 * Asthma and Allergy Research Associates, PC, Normal, Illinois. † Asthma, Nasal Disease & Allergy Research of New England, Providence, Rhode Island. ‡ Princeton Allergy & Asthma Research, Princeton, New Jersey. § Milwaukee Medical Clinic, Advanced Healthcare, SC, Milwaukee, Wisconsin. ¶ Allergy & Asthma Medical Group & Research Center, APC, San Diego, California. 储 University of Wisconsin Clinical Sciences Center, Madison, Wisconsin. ** Johns Hopkins Medical Institutions, Baltimore, Maryland. †† Schering-Plough Research Institute, Kenilworth, New Jersey. ‡‡ Members of the Nasonex Sinusitis Group are listed in the Acknowledgment section. Supported by the Schering-Plough Research Institute, Kenilworth, New Jersey. Received for publication October 29, 2001. Accepted for publication in revised form December 18, 2001.
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Rhinosinusitis is usually preceded by an inflammation of the mucosa of one or more of the paranasal sinuses associated with a viral upper respiratory tract infection or an allergic reaction. Inflammation can lead to obstruction of the sinus ostia, retention of secretions, and bacterial invasion.2,4 –7 The obstruction, mucus retention, and infection produce the signs and symptoms characteristic of rhinosinusitis, including purulent rhinorrhea, purulent pharyngeal draining, and cough that persist beyond the 7 to 10 days typical of an upper respiratory tract viral infection. Additional symptoms may include nasal congestion, headache, or facial pain. The diagnosis of rhinosinusitis can be confirmed by sinus imaging with coronal computed tomography (CT). Acute rhinosinusitis is currently defined as an inflammation of the sinuses with the symptom complex lasting less than 8 weeks in adults and less than 12 weeks in children.1 With appropriate therapy, the signs and symptoms of acute rhinosinusitis usually resolve completely.8 The goals of treatment for rhinosinusitis are to eradicate the bacterial pathogens, stop the tissue-damaging inflammatory process, and promote sinus drainage.1,7,8 Usually, antibiotics are given to control the bacterial infection. The addition of topical washings, expectorants, and decongestants may improve sinus clearance. Topical corticosteroids can be used to reduce mu-
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cosal swelling and facilitate drainage, reduce eosinophilia in inflamed tissues,9 and shrink nasal polyps,10 making them potentially useful in rhinosinusitis management. In addition, the efficacy of intranasal corticosteroids has been consistently demonstrated for seasonal allergic rhinitis and moderate-tosevere exacerbations of perennial rhinitis, possible predisposing factors to the development of acute rhinosinusitis. Although guidelines reflect the belief of many clinicians that intranasal corticosteroids are a valuable component of rhinosinusitis management,1,5,7,8 limited clinical data are available on their use in this disease. Three studies that evaluated the effectiveness of intranasal corticosteroids as adjuncts to antibiotic therapy demonstrated significant symptomatic improvement compared with the antibiotic/placebo control used in each trial. However, each study evaluated ⬍90 patients, used different antibiotics, and administered the intranasal corticosteroid for varying periods of time, up to 3 months.8,11,12 In a fourth study of 180 patients, significant relief of symptoms was reported after 3 weeks of adjunctive intranasal corticosteroid treatment.13 Mometasone furoate is a potent, topically active, synthetic corticosteroid, which has been formulated for dermatologic use and also formulated as a nasal spray (MFNS; Nasonex, Schering, Kenilworth, NJ) approved for the treatment of seasonal and perennial allergic rhinitis in adults and children. In a previous study in patients with recurrent rhinosinusitis, adjunctive therapy with MFNS 400 g, twice daily, reduced significantly and more rapidly the symptoms of rhinosinusitis compared with the antibiotic/placebo control.14 The objective of the present placebo-controlled clinical trial is to evaluate the effectiveness and safety of adjunctive therapy with MFNS in a broader population of patients with acute rhinosinusitis, rather than only recurrent rhinosinusitis, and to compare the use of MFNS 200 g, twice daily, with a higher dose, 400 g, twice daily, and placebo. These results have been presented in preliminary form.15 METHODS Study Design This study was a 21-day, randomized, double-blinded, placebo-controlled trial conducted at 61 treatment centers in the United States. Patients aged ⱖ12 years with symptoms characteristic of an acute episode of rhinosinusitis were evaluated for inclusion in the trial. The protocol was approved by the institutional review board at each treatment center, and written informed consent was obtained from each patient or from the parent or guardian for each patient under 18 years of age. Medical history and physical examination included vital signs, including blood pressure, complete blood count, blood chemistries, urinalysis, electrocardiogram, and nasal examination, and ensured that each patient was free of other clinically significant diseases. Patients were excluded for expected immediate sinus or nasal surgery, cystic fibrosis, nasal polyps, Kartagener syndrome, glaucoma, or a history of subcapsular cataracts. Intranasal or systemic corti-
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costeroids, decongestants, and systemic antibiotics were excluded for varying periods of washout time before the baseline visit. For evaluation of hypothalamic-pituitary-adrenal (HPA) axis function, patients at 18 of the 61 study sites were required to have a baseline, unstimulated plasma cortisol level ⱖ5 g/dL and a level ⱖ18 g/dL after a 30-minute stimulation with cosyntropin (Cortrosyn, Organon, Inc, West Orange, NJ), a synthetic form of adrenocorticotropic hormone. At baseline (day 1) and day 21, six symptoms (purulent rhinorrhea, stuffiness/congestion, postnasal drip, sinus headache, facial pain, and cough) were evaluated by both the investigator and the patient according to the following scale: 0 ⫽ none (symptoms were not present); 1 ⫽ mild (symptoms present but causing little or no discomfort); 2 ⫽ moderate (symptoms present, annoying and causing discomfort); and 3 ⫽ severe (symptoms very marked and interfering with daily activities). For patients to be eligible for randomization, the total symptoms score (TSS) was to be ⱖ6. At least one nasal symptom was to be moderate or severe, and purulent rhinorrhea was to be present. Limited coronal paranasal CT scans read by a radiologist at each study site at the baseline visit had to show evidence of rhinosinusitis (judged as clinically significant mucosal thickening, opacification, or air/fluid levels) in one or more sinuses to satisfy inclusion criteria. Eligible patients who satisfied the inclusion and exclusion criteria received 21 days of treatment with the antibiotic amoxicillin/clavulanate potassium (ACP; Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, and were randomized to receive MFNS 200 g, twice daily, MFNS 400 g, twice daily, or matching placebo in a 1:1:1 ratio. The antibiotic treatment was chosen based on the fact that it is the most widely used treatment for rhinosinusitis and it is efficacious against the most probable infecting pathogens, including Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.16 Further, a previous study13 showed that ACP was effective for treatment in this setting. To increase the likelihood of bacterial eradication, ACP 875 mg, twice daily, was given for 21 days rather than the generally prescribed 10 to 14 days. Concurrent medications that would have interfered with the evaluations were not allowed, including any form of corticosteroids, nasal decongestants, or antihistamines. Patient adherence to therapy was confirmed by weighing the nasal spray dosing containers without the patient’s knowledge. Patients were instructed to evaluate their symptoms for the previous 12 hours in a diary twice daily (AM and PM). Patients also recorded their use of study medication, other medications, and any adverse events that they experienced. Patient diaries were used for the entire 21 days of treatment. Day 21 included an overall evaluation of rhinosinusitis by the investigator using the four-point scale described previously for use by patients and investigators on day 1 and evaluation by the patients of the therapeutic response accord-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
ing to the following scale: 1 ⫽ complete relief (virtually no symptoms present); 2 ⫽ marked relief (symptoms greatly improved but scarcely troublesome); 3 ⫽ moderate relief (symptoms present and possibly troublesome but noticeably improved); 4 ⫽ slight relief (symptoms present and improved only minimally); and 5 ⫽ no relief (symptoms unchanged or worse than at baseline). Included in the evaluation of safety was an evaluation of potential changes in HPA axis function in patients from 18 treatment centers. On days 1 and 21, plasma cortisol concentrations were determined in blood samples drawn at 8:00 AM (⫾ 1 hour), before adrenal stimulation with an intravenous injection of 0.25 mg cosyntropin. Postcosyntropin plasma cortisol concentrations were determined 30 minutes after the injection. CT scans of the paranasal sinuses were made at baseline (day 1) and at day 21 and evaluated by an independent radiologist who was blinded to the treatment assignment of the patient and temporal order of the scans. Each sinus (frontal, maxillary, posterior ethmoid, and sphenoid) was scored on the level of opacity, which takes into account mucosal thickening and air/fluid level: up to 25% opacification was given a score ⫽ 0, and more than 25% opacification was given a score ⫽ 1. The frontal recess, middle meatus, and infundibulum were rated as 0 ⫽ patent and 1 ⫽ obstructed; agger nasi cell, ethmoid bulla, and sinus lateralis were rated as 0 ⫽ nonopacified and 1 ⫽ opacified. The total score was then defined as the sum of the individual scores (range 0 to 10). Note that a total score of zero does not imply that no sinus abnormality was present, as it still allows for up to 25% opacification of any of the frontal, maxillary, posterior ethmoid, or sphenoid sinuses. In addition to this scoring, the frontal, maxillary, posterior ethmoid, and sphenoid sinuses were separately rated for opacification: 0 ⫽ up to 25%; 1 ⫽ up to 50%; 2 ⫽ up to 75%; and 3 ⫽ total opacification. This separate scoring allowed for greater weighting of the larger sinuses.
Statistical Methods The primary efficacy variable was defined as the change from baseline in mean TSS as recorded twice daily over day 1 through day 15 in the patient’s diary. Two-way analysis of variance (ANOVA) was used to extract effects attributable to treatment and center, contrasting the least-squares means of MFNS doses and placebo using a 5% significance level. Similar analyses were made for day 1 through day 21 and for individual symptom scores as secondary efficacy variables. Patients’ evaluations of their responses to treatment on day 21 and investigators’ evaluations of patient responses were also analyzed by the same ANOVA noted above. Subjective evaluation of therapeutic responses to treatment was analyzed by the 2 test. The ANOVA model described above also analyzed plasma cortisol concentration data from the cosyntropin stimulation tests. RESULTS Patient Characteristics A total of 967 patients met the initial evaluation criteria and were randomized to 1 of the 3 treatment groups: ACP with MFNS 200 g, twice daily (n ⫽ 318); ACP with MFNS 400 g, twice daily (n ⫽ 324); and ACP with placebo (n ⫽ 325). There were no clinically relevant differences in demographic characteristics among the three treatment groups, and baseline symptom data were comparable (Table 1). The final inclusion criterion was radiographic evidence of rhinosinusitis on CT scan at baseline. Because this measurement introduced a lag time, some patients were started on treatments but discontinued from the study when CT data failed to show evidence of disease. The patient subset who met the inclusion criteria had CT scan confirmation of disease, available postbaseline diary data, at least 80% compliance with study medication, and at least 7 days of treatment made up the efficacy-evaluable population of 864 (Table 1, baseline symptom scores) for primary efficacy analysis. The reasons
Table 1. Demographic and Baseline Symptomatology Data
Age (yr)* (range 8–78) Male/female (%) Weight (lb)* Baseline total symptom score* Individual symptom scores*: Congestion Facial pain Headache Purulent rhinorrhea Postnasal drip Cough
Placebo (n ⴝ 325)
MFNS 200 g, twice daily (n ⴝ 318)
MFNS 400 g, twice daily (n ⴝ 324)
38.0 39/61 174.1 11.61 (n ⫽ 290)
39.4 42/58 172.0 11.57 (n ⫽ 282)
39.8 44/56 175.4 11.61 (n ⫽ 292)
2.34 1.79 1.87 2.04 2.17 1.39
2.35 1.83 1.79 1.99 2.20 1.41
2.28 1.89 1.82 2.02 2.11 1.49
* Mean values. Note: The mean values of baseline individual symptom scores and baseline TSS are based on the efficacy-evaluable subset of patients. This subset is used for the primary efficacy analysis.
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for discontinuation or exclusion were evenly distributed among the groups. Efficacy TSSs. Figure 1 illustrates that addition of MFNS 200 g or 400 g, twice daily, to ACP treatment of acute rhinosinusitis significantly improved the mean TSS for patients averaged over the period of day 1 through day 15 compared with ACP with placebo (primary efficacy variable). The mean TSS for patients receiving MFNS 200 g, twice daily, decreased from baseline by 5.89 (50%), compared with a decrease of 5.22 (44%) in patients receiving placebo (P ⫽ 0.014). Mean TSS for patients taking MFNS 400 g, twice daily, decreased by 5.86 (51%) averaged over the period of day 1 through day 15 (P ⫽ 0.017 compared with placebo). Significant improvement in TSS was also observed over the course of the entire 21-day treatment. Averaged over the period of days 1 through 21 of treatment, MFNS 200 g, twice daily, and 400 g, twice daily, produced a decrease of 6.44 (54%) and 6.51 (56%), respectively, whereas placebo showed a decrease of 5.86 (50%; P ⫽ 0.031 and P ⫽ 0.016, respectively, compared with placebo). Individual symptom scores. Individual symptom scores showed consistently greater improvement for patients treated with either dose of MFNS during treatment with ACP compared with placebo. Symptoms associated with inflammatory swelling, such as stuffiness and facial pain, were particularly better relieved by MFNS (Fig 2). The reduction in scores for stuffiness/congestion was significantly greater for patients treated with MFNS 200 g, twice daily, or 400 g, twice daily, averaged over the period of days 1 through 15 compared with placebo (P ⫽ 0.01 and P ⫽ 0.025, respectively). In addition, MFNS 400 g, twice daily, gave significantly greater relief of facial pain compared with placebo (P ⫽ 0.008). Further, Figure 2 shows added reduction of secretory symptoms, including postnasal drip, with MFNS 200 g, twice daily (P ⫽ 0.038 vs placebo) and rhinorrhea with MFNS 400 g, twice daily (P ⫽ 0.045 vs placebo). Relief of cough and sinus headache was comparable for all treatment groups (Fig 2).
Figure 1. Improvement in TSSs averaged over days 1 through 15, and days 1 through 21 of treatment. bid, twice daily.
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Figure 2. Improvement in individual symptom scores for inflammatory symptoms (congestion, facial pain/pressure/tenderness, and sinus headache) and secretory symptoms (purulent rhinorrhea, postnasal drip, and cough) averaged over days 1 through 15 of treatment. bid, twice daily.
Day 21 evaluations of response to treatment. Physician evaluations of symptoms of rhinosinusitis at day 21 were generally consistent with the averaged patient-recorded evaluations reported above. The physician evaluations found significant improvement in scores for stuffiness/congestion for patients receiving MFNS 200 g, twice daily (62%), or MFNS 400 g, twice daily (64%), compared with placebo (50%; P ⫽ 0.001 and P ⫽ 0.008, respectively). Adjunctive MFNS 400 g, twice daily, was also associated with greater reduction in the symptom score for purulent rhinorrhea (81% vs 72% for placebo; P ⫽ 0.015) and facial pain/pressure/ tenderness (74% vs 68% for placebo; P ⫽ 0.039). Patient evaluations of overall response to treatment at day 21 showed that MFNS 200 g or 400 g, twice daily, with ACP was significantly more effective than placebo with ACP (P ⱕ 0.005). Complete or marked relief was reported by 63% and 66% of patients treated with MFNS 200 g or 400 g, twice daily, respectively, compared with 55% in patients treated with placebo. Finally, physicians’ evaluation of their patients’ overall condition of rhinosinusitis showed that the addition of MFNS 200 g, twice daily, or 400 g, twice daily, to antibiotic therapy improved (reduced) the scores of the overall rhinosinusitis condition by 60% and 61%, respectively, compared with a reduction of 53% with placebo (P ⱕ 0.006). Onset of relief. Day-by-day analysis showed significant improvements of TSSs over placebo treatment as early as day 4 for patients receiving MFNS 200 g or 400 g, twice daily, as adjunctive therapy, indicating a rapid onset of relief (Fig 3A). Relief of individual symptoms showed a similar pattern. For example, the inflammatory symptom of stuffiness/congestion was significantly improved over placebo for patients receiving MFNS 200 g or 400 g, twice daily, as early as day 4 (Fig 3B).
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Figure 3. (A) Improvement in daily TSSs during days 1 through 15 of treatment. (B) Improvement in daily congestion scores during days 1 through 15 of treatment. bid, twice daily.
Evaluation of changes in CT scans of sinuses. Complete data on all 10 anatomical sites for scoring CT scans were available for 563 patients. At day 21, greater proportions of patients in the MFNS 200 g and 400 g, twice daily, treatment groups had total scores ⫽ 0 (34% and 34.5%, respectively) compared with the placebo group (29.6%). However, the mean change in score from baseline to day 21 did not differ statistically significantly among the three treatment groups. Evaluation of Safety Adverse events. Treatment with MFNS 200 g or 400 g, twice daily, and ACP 875 mg, twice daily, for 21 days was well tolerated, and most adverse events that were reported were of mild or moderate intensity. The incidence of treatment-related adverse events was similar for all three treatment groups: 12% for ACP and MFNS 200 g, twice daily, 15% for ACP and MFNS 400 g, twice daily, and 15% for ACP and placebo. The most frequently reported adverse event considered related to treatment was epistaxis (Table 2). Other local adverse events, including nasal burning, nasal irritation, and headache, occurred in ⱕ2% of patients in any treatment group. Fifty patients discontinued treatment because of adverse events, most commonly diarrhea and nausea because of ACP. These patients were equally distributed among the three treatment groups. Epistaxis, nasal irritation, nasal burning, or infection were not a cause of discontinuation for any patient. No clinically meaningful changes in mean values for clinical laboTable 2. Treatment-Related Adverse Events Occurring in ⱖ2% of Patients
Epistaxis* Nasal burning Nasal irritation Headache
Placebo (n ⴝ 325)
MFNS 200 g, twice daily (n ⴝ 318)
MFNS 400 g, twice daily (n ⴝ 324)
6% 2% 0 2%
5% 1% ⬍1% 2%
6% 1% 2% 1%
* Epistaxis included mild events, such as blood-tinged mucus or crusting/bleeding.
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ratory determinations were found, and no clinically significant abnormal laboratory values were noted for any subject. Cosyntropin stimulation test results. At 18 study sites the response to cosyntropin stimulation was analyzed as the difference between poststimulation and prestimulation plasma cortisol concentrations. Measurements made at baseline and on day 21 found no clinically relevant decreases in mean basal or stimulated plasma cortisol levels in any treatment group. No statistically significant differences were observed between groups in prestimulation and poststimulation cortisol values (Table 3). DISCUSSION Recent practice guidelines for the diagnosis and management of rhinosinusitis suggest considering the use of an intranasal corticosteroid as adjunctive therapy.5 Two essential components of rhinosinusitis management are the eradication of bacterial pathogens and the inhibition of the inflammatory process. Treatment of rhinosinusitis with standard antibiotic therapy eliminates the bacterial infection, whereas adjunctive use of an intranasal corticosteroid, such as MFNS, locally inhibits the inflammatory process.7,8,17,18 However, until recently, only a few studies have evaluated the effectiveness of the addition of an intranasal corticosteroid to standard antibiotic therapy. In a recent report of more than 400 patients with recurrent rhinosinusitis, adjunctive therapy with MFNS 400 g, twice daily, was effective in relieving rhinosinusitis symptoms, particularly those related to inflammatory swelling (ie, congestion, facial pain, and headache) compared with the antibiotic ACP with placebo.14 Recurrent rhinosinusitis may involve an underlying chronic inflammation with attendant worsening during acute episodes. Compared with ACP/placebo, the additional relief of symptoms of recurrent rhinosinusitis provided by the use of adjunctive MFNS seemed to develop over 6 to 7 days.14 Thus, the relief of recurrent rhinosinusitis by adjunctive MFNS may develop more slowly than relief of acute rhinosinusitis. The population for the current study was selected solely on the basis of presentation with acute rhinosinusitis, in contrast to the earlier study of adjunctive MFNS in patients with a history of recurrent acute rhinosinusitis. However, in both
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Table 3. Mean Concentrations of Morning Plasma Cortisol Before and After Cosyntropin Stimulation, at Baseline, and After 21 Days of Treatment MFNS 200 g, twice daily (n ⴝ 72)
Placebo (n ⴝ 75)
Prestimulation Poststimulation Poststimulation minus prestimulation
Baseline g/dL
Day 21 g/dL
Baseline g/dL
Day 21 g/dL
Baseline g/dL
Day 21 g/dL
15.9 29.9 14.0
15.6 29.8 14.2
15.4 29.8 14.4
14.3 27.5 13.3
15.4 30.0 14.6
14.8 28.6 13.8
studies, patients were required to have a CT scan reflective of rhinosinusitis. The present study of more than 900 patients with moderate symptoms of acute rhinosinusitis shows that the addition of either MFNS 200 g or 400 g, twice daily, to standard antibiotic therapy also provides significantly greater relief of symptoms, particularly stuffiness/congestion and facial pain, than antibiotic with placebo. Further, the greater relief of rhinosinusitis symptoms afforded by either dosage of MFNS adjunctive therapy was seen as by day 4 of treatment, indicating that MFNS in combination with ACP provided faster relief of rhinosinusitis symptoms compared with ACP/placebo treatment. Although no statistically significant differences in the efficacy of the two MFNS doses were detected, significant improvements in symptom scores were more consistently reported with MFNS 400 g, twice daily, than with MFNS 200 g, twice daily. Adjunctive MFNS 400 g, twice daily, provided rapid onset of relief of the symptom of congestion and stuffiness. This relief was also reflected in the time-averaged scores, both during the early phase of treatment (days 1 through 15) and throughout the entire 21-day course of treatment. Such data indicate the importance of the anti-inflammatory action of MFNS in treating the acute rhinosinusitis. Despite the improvements in symptoms with MFNS treatment, radiologic evaluation showed no statistically significant differences in CT scan images among treatment groups. Thus, in these patients radiologic evidence of underlying inflammation may persist beyond resolution of symptoms of rhinosinusitis. Both dosages of MFNS, 200 g and 400 g, twice daily, were well tolerated. Plasma cortisol responses to cosyntropin stimulation further indicated that 21-day treatment with MFNS 200 g or 400 g, twice daily, had no suppressive effect on the HPA axis. These findings are consistent with the data from clinical trials of the treatment of allergic rhinitis, which have already demonstrated MFNS to be effective and well tolerated at dosages of up to 200 g daily.19 –26 Further, studies of MFNS in adults and children with allergic rhinitis showed both a lack of HPA axis suppression and of childhood growth suppression and are consistent with extremely low bioavailability of mometasone furoate after intranasal administration.19,27,28 The results of this 21-day placebo-controlled study support the current clinical rationale of adding an intranasal cortico-
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MFNS 400 g, twice daily (n ⴝ 70)
steroid to antibiotic therapy of acute episodes of rhinosinusitis. In particular, the onset of relief of symptoms by MFNS with ACP was rapid and significantly faster than that observed for ACP with placebo. MFNS was effective and well tolerated at dosages of up to 400 g, twice daily, and there was no evidence of HPA axis suppression after adjunctive treatment with MFNS. ACKNOWLEDGMENTS The members of the Nasonex Sinusitis Group are as follows: Jeffrey Adelglass, MD, Research Across America, Dallas, TX; James N. Baraniuk, MD, Georgetown University Medical Center, Washington, DC; William Berger, MD, Southern California Research Center, Mission Viejo, CA; Robert Berkowitz, MD, Atlanta Allergy and Immunology Research Foundation, Atlanta, GA; David Bernstein, MD, Bernstein Clinical Research Center, Cincinnati, OH; Edwin Bronsky, MD, Intermountain Clinical Research, Salt Lake City, UT; William W. Busse, MD, University of Wisconsin Clinical Science Center, Madison, WI; Thomas B. Casale, MD, Nebraska Medical Research Institute, Papillion, NE; Christopher M. Chappel, MD, Family Practice Associates, Kissimmee, FL; B. Lauren Charous, MD, Milwaukee Medical Clinic, Milwaukee, WI; Theodore J. Chu, MD, San Jose, CA; Robert M. Cohen, MD, The Allergy & Asthma Clinical Research Center, LLC, Lawrenceville, GA; Jonathan Corren, MD, Allergy Research Foundation, Inc, Los Angeles, CA; Joseph David Diaz, MD, Allergy and Asthma Research Center, San Antonio, TX; David Dobratz, MD, IMTGI/College Park Family Care, Overland Park, KS; Albert F. Finn, MD, Allergy & Asthma Centers of Charleston, Charleston, SC; John W. Georgitis, MD, Bowman Gray School of Medicine, Winston-Salem, NC; Trevor I. Goldberg, MD, Charlotte Eye Ear Nose & Throat Associates, PA, Charlotte, NC; Marc F. Goldstein, MD, Larchmont Medical Center II, Mt. Laurel, NJ; David L. Goodman, MD, InSite Clinical Trials, Denver, CO; Gary N. Gross, MD, Pharmaceutical Research & Consulting, Inc, Dallas, TX; Jay Grossman, MD, Vivra Research Partners, Tucson, AZ; Robert E. Grubbe, MD, Anniston Medical Clinic, Anniston, AL; Frank C. Hampel, Jr, MD, Central Texas Health Research, New Braunfels, TX; David Jennings, MD, Research Memphis, Memphis, TN; Harold B. Kaiser, MD, Clinical Study Center, Allergy & Asthma Specialists, PA, Minneapolis, MN; George W. Kern, V, MD,
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Allergy, Asthma, & Clinical Immunology of Chester County, Ltd, West Chester, PA; Michael Lawrence, MD, Center for Clinical Research, Taunton, MA; Allen K. Lieberman, MD, HealthQuest Therapy and Research Institute, Austin, TX; W. R. Lumry, MD, Asthma & Allergy Research Associates, Dallas, TX; Clement A. Maccia, MD, Allergy & Asthma Care Clinical Research Center, Warren, NJ; Eli O. Meltzer, Allergy & Asthma Medical Group & Research Center, APC, San Diego, CA; S. David Miller, New England Research Center, Inc, N. Dartmouth, MA; Anjuli S. Nayak, MD, Asthma and Allergy Research Associates, Normal, IL; Nicholas Nayak, MD, Asthma and Allergy Research Associates, Normal, IL; Michael J. Noonan, MD, Allergy Associates Research Center, Portland, OR; Richard J. Perrotta, MD, Stuart, FL; Frank Picone, MD, Allergy & Asthma Consultants, PA, Tinton Falls, NJ; Warren W. Pleskow, MD, Encinitas, CA; Bruce M. Prenner, MD, Allergy Associates Medical Group, Inc, San Diego, CA; Paul H. Ratner, MD, Sylvana Research, San Antonio, TX; John G. Riehm, MD, Kentuckiana Allergy, PSC, Louisville, KY; Jeffrey B. Rosen, MD, Clinical Research of South Florida, Coral Gables, FL; Michael Rowe, MD, Michigan Respiratory Health and Research Institute, Novi, MI; Eric J. Schenkel, MD, Valley Clinical Research Center, Easton, PA; Jeffery L. Schul, MD, Virginia Allergy, Pulmonary and Asthma Research Center, Richmond, VA; Jay E. Selcow, MD, Connecticut Asthma & Allergy Center, West Hartford, CT; James M. Seltzer, MD, Health Advance Institute, Inc, San Diego, CA; Guy A. Settipane, MD, Asthma, Nasal Disease, & Allergy Research of New England, Providence, RI; Mark H. Shapiro, MD, Palomar Medical Group, Escondido, CA; Larry J. Shemen, MD, New York, NY; Tommy C. Sim, MD, Family Center for Asthma & Allergic Diseases, Friendswood, TX; Raymond G. Slavin, MD, St. Louis University School of Medicine, St. Louis, MO; C. Steven Smith, MD, SFI Research Labs Clinical Division, Louisville, KY; G. Edward Stewart, II, MD, Allergy and Asthma Care of Florida Clinical Research Division, Ocala, FL; James M. Sumerson, MD, Staffordshire Professional Center, Voorhees, NJ; Catherine M. VanKerckhove, MD, Colorado Allergy and Asthma Centers, PC, Aurora, CO; D. Robert Webb, MD, Allergy and Asthma Associates, Kirkland, WA; Michael Wein, MD, Doctor’s Clinic, Vero Beach, FL; Martha V. White, MD, Institute for Asthma and Allergy at Washington Hospital Center, Washington, DC; David L. Williams, MD, Atlantic Institute of Clinical Research, Daytona Beach, FL; Paul V. Williams, MD, ASTHMA, Inc, Mt. Vernon, WA; and John A. Winder, MD, Allergy and Asthma Research Center, Sylvania, OH. REFERENCES 1. Kaliner MA, Osguthorpe JD, Fireman P, et al. Sinusitis: bench to bedside. Current findings, future directions. J Allergy Clin Immunol 1997;99:S829 –S848. 2. Shapiro GG, Rachelefsky GS. Introduction and definition of sinusitis. J Allergy Clin Immunol 1992;90:417– 418. 3. Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures
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for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol 1999;103:408 – 414. Druce HM. Diagnosis of sinusitis in adults: history, physical examination, nasal cytology, echo, and rhinoscope. J Allergy Clin Immunol 1992;90:436 – 441. Spector SL, Bernstein IL, Li JT, et al. Parameters for the diagnosis and management of sinusitis. J Allergy Clin Immunol 1998;102:S107–S144. Newman LJ, Platts-Mills TA, Phillips CD, et al. Chronic sinusitis. Relationship of computed tomographic findings to allergy, asthma, and eosinophilia. JAMA 1994;271:363–367. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg 1997;117: S41–S49. Qvarnberg Y, Kantola O, Salo J, et al. Influence of topical steroid treatment on maxillary sinusitis. Rhinology 1992;30: 103–112. Meltzer EO, Jalowayski AA, Orgel HA, Harris AG. Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of therapy with mometasone furoate nasal spray. J Allergy Clin Immunol 1998;102:39 – 49. Mygind N. Advances in the medical treatment of nasal polyps. Allergy 1999;54(Suppl):12–16. Cuenant G, Stipon JP, Plante-Longchamp G, et al. Efficacy of endonasal neomycin-tixocortol pivalate irrigation in the treatment of chronic allergic and bacterial sinusitis. ORL J Otorhinolaryngol Relat Spec 1986;48:226 –232. Barlan IB, Erkan E, Bakir M, et al. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children. Ann Allergy Asthma Immunol 1997;78:598 – 601. Meltzer EO, Orgel HA, Backhaus JW, et al. Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis. J Allergy Clin Immunol 1993;92:812– 823. Meltzer EO, Charous BL, Busse WW, et al. Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray. The Nasonex Sinusitis Group. J Allergy Clin Immunol 2000;106:630 – 637. Charous BL, Meltzer EO, Busse WW, et al. Adjunctive treatment of acute sinusitis with mometasone furoate nasal spray-a comparison of two dose regimens. J Allergy Clin Immunol 2000;105:S210. Chow AW, Hall CB, Klein JO, et al. Evaluation of new antiinfective drugs for the treatment of respiratory tract infections. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15(Suppl):S62–S88. Schleimer RP. An overview of glucocorticoid anti-inflammatory actions. Eur J Clin Pharmacol 1993;45:S3–S7,S43–S44. Barton BE, Jakway JP, Smith SR, Siegel MI. Cytokine inhibition by a novel steroid, mometasone furoate. Immunopharmacol Immunotoxicol 1991;13:251–261. Davies RJ, Nelson HS. Once-daily mometasone furoate nasal spray: efficacy and safety of a new intranasal glucocorticoid for allergic rhinitis. Clin Ther 1997;19:27–38. Hebert JR, Nolop K, Lutsky BN. Once-daily mometasone furoate aqueous nasal spray (Nasonex) in seasonal allergic rhinitis: an active- and placebo-controlled study. Allergy 1996; 51:569 –576. Graft D, Aaronson D, Chervinsky P, et al. A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray. J Allergy Clin Immunol 1996;98:724 –731.
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22. Bronsky EA, Aaronson DW, Berkowitz RB, et al. Dose ranging study of mometasone furoate (Nasonex) in seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1997;79:51–56. 23. 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. Ann Allergy Asthma Immunol 1997;79:370 –378. 24. Meltzer EO, Berger WE, Berkowitz RB, et al. A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis. J Allergy Clin Immunol 1999; 104:107–114. 25. Drouin M, Yang WH, Bertrand B, et al. Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclomethasone dipropionate for treating perennial allergic rhinitis patients. Ann Allergy Asthma Immunol 1996;77:153–160. 26. Berkowitz RB, Roberson S, Zora J, et al. Mometasone furoate nasal spray is rapidly effective in the treatment of seasonal
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allergic rhinitis in an outdoor (park), acute exposure setting. Allergy Asthma Proc 1999;20:167–172. 27. Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children. Clin Ther 1997;19:1330 –1339. 28. Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics 2000;105:E22. Requests for reprints should be addressed to: Anjuli S. Nayak, MD Asthma & Allergy Research Associates, PC 1300 Franklin Avenue, #180 Normal, IL 61761 E-mail: [email protected]
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INTRODUCTION Rhinosinusitis is a common disease which can have a troublesome impact on daily life, affecting an estimated 35 million Americans annually, and causing a significant clinical and economic burden.1–3 Recent estimates place annual rhinosinusitis-related health care expenditures in excess of US$6 billion, with ⬎50% of that amount attributed to a primary diagnosis of acute or chronic rhinosinusitis.3 * Asthma and Allergy Research Associates, PC, Normal, Illinois. † Asthma, Nasal Disease & Allergy Research of New England, Providence, Rhode Island. ‡ Princeton Allergy & Asthma Research, Princeton, New Jersey. § Milwaukee Medical Clinic, Advanced Healthcare, SC, Milwaukee, Wisconsin. ¶ Allergy & Asthma Medical Group & Research Center, APC, San Diego, California. 储 University of Wisconsin Clinical Sciences Center, Madison, Wisconsin. ** Johns Hopkins Medical Institutions, Baltimore, Maryland. †† Schering-Plough Research Institute, Kenilworth, New Jersey. ‡‡ Members of the Nasonex Sinusitis Group are listed in the Acknowledgment section. Supported by the Schering-Plough Research Institute, Kenilworth, New Jersey. Received for publication October 29, 2001. Accepted for publication in revised form December 18, 2001.
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Rhinosinusitis is usually preceded by an inflammation of the mucosa of one or more of the paranasal sinuses associated with a viral upper respiratory tract infection or an allergic reaction. Inflammation can lead to obstruction of the sinus ostia, retention of secretions, and bacterial invasion.2,4 –7 The obstruction, mucus retention, and infection produce the signs and symptoms characteristic of rhinosinusitis, including purulent rhinorrhea, purulent pharyngeal draining, and cough that persist beyond the 7 to 10 days typical of an upper respiratory tract viral infection. Additional symptoms may include nasal congestion, headache, or facial pain. The diagnosis of rhinosinusitis can be confirmed by sinus imaging with coronal computed tomography (CT). Acute rhinosinusitis is currently defined as an inflammation of the sinuses with the symptom complex lasting less than 8 weeks in adults and less than 12 weeks in children.1 With appropriate therapy, the signs and symptoms of acute rhinosinusitis usually resolve completely.8 The goals of treatment for rhinosinusitis are to eradicate the bacterial pathogens, stop the tissue-damaging inflammatory process, and promote sinus drainage.1,7,8 Usually, antibiotics are given to control the bacterial infection. The addition of topical washings, expectorants, and decongestants may improve sinus clearance. Topical corticosteroids can be used to reduce mu-
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cosal swelling and facilitate drainage, reduce eosinophilia in inflamed tissues,9 and shrink nasal polyps,10 making them potentially useful in rhinosinusitis management. In addition, the efficacy of intranasal corticosteroids has been consistently demonstrated for seasonal allergic rhinitis and moderate-tosevere exacerbations of perennial rhinitis, possible predisposing factors to the development of acute rhinosinusitis. Although guidelines reflect the belief of many clinicians that intranasal corticosteroids are a valuable component of rhinosinusitis management,1,5,7,8 limited clinical data are available on their use in this disease. Three studies that evaluated the effectiveness of intranasal corticosteroids as adjuncts to antibiotic therapy demonstrated significant symptomatic improvement compared with the antibiotic/placebo control used in each trial. However, each study evaluated ⬍90 patients, used different antibiotics, and administered the intranasal corticosteroid for varying periods of time, up to 3 months.8,11,12 In a fourth study of 180 patients, significant relief of symptoms was reported after 3 weeks of adjunctive intranasal corticosteroid treatment.13 Mometasone furoate is a potent, topically active, synthetic corticosteroid, which has been formulated for dermatologic use and also formulated as a nasal spray (MFNS; Nasonex, Schering, Kenilworth, NJ) approved for the treatment of seasonal and perennial allergic rhinitis in adults and children. In a previous study in patients with recurrent rhinosinusitis, adjunctive therapy with MFNS 400 g, twice daily, reduced significantly and more rapidly the symptoms of rhinosinusitis compared with the antibiotic/placebo control.14 The objective of the present placebo-controlled clinical trial is to evaluate the effectiveness and safety of adjunctive therapy with MFNS in a broader population of patients with acute rhinosinusitis, rather than only recurrent rhinosinusitis, and to compare the use of MFNS 200 g, twice daily, with a higher dose, 400 g, twice daily, and placebo. These results have been presented in preliminary form.15 METHODS Study Design This study was a 21-day, randomized, double-blinded, placebo-controlled trial conducted at 61 treatment centers in the United States. Patients aged ⱖ12 years with symptoms characteristic of an acute episode of rhinosinusitis were evaluated for inclusion in the trial. The protocol was approved by the institutional review board at each treatment center, and written informed consent was obtained from each patient or from the parent or guardian for each patient under 18 years of age. Medical history and physical examination included vital signs, including blood pressure, complete blood count, blood chemistries, urinalysis, electrocardiogram, and nasal examination, and ensured that each patient was free of other clinically significant diseases. Patients were excluded for expected immediate sinus or nasal surgery, cystic fibrosis, nasal polyps, Kartagener syndrome, glaucoma, or a history of subcapsular cataracts. Intranasal or systemic corti-
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costeroids, decongestants, and systemic antibiotics were excluded for varying periods of washout time before the baseline visit. For evaluation of hypothalamic-pituitary-adrenal (HPA) axis function, patients at 18 of the 61 study sites were required to have a baseline, unstimulated plasma cortisol level ⱖ5 g/dL and a level ⱖ18 g/dL after a 30-minute stimulation with cosyntropin (Cortrosyn, Organon, Inc, West Orange, NJ), a synthetic form of adrenocorticotropic hormone. At baseline (day 1) and day 21, six symptoms (purulent rhinorrhea, stuffiness/congestion, postnasal drip, sinus headache, facial pain, and cough) were evaluated by both the investigator and the patient according to the following scale: 0 ⫽ none (symptoms were not present); 1 ⫽ mild (symptoms present but causing little or no discomfort); 2 ⫽ moderate (symptoms present, annoying and causing discomfort); and 3 ⫽ severe (symptoms very marked and interfering with daily activities). For patients to be eligible for randomization, the total symptoms score (TSS) was to be ⱖ6. At least one nasal symptom was to be moderate or severe, and purulent rhinorrhea was to be present. Limited coronal paranasal CT scans read by a radiologist at each study site at the baseline visit had to show evidence of rhinosinusitis (judged as clinically significant mucosal thickening, opacification, or air/fluid levels) in one or more sinuses to satisfy inclusion criteria. Eligible patients who satisfied the inclusion and exclusion criteria received 21 days of treatment with the antibiotic amoxicillin/clavulanate potassium (ACP; Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, and were randomized to receive MFNS 200 g, twice daily, MFNS 400 g, twice daily, or matching placebo in a 1:1:1 ratio. The antibiotic treatment was chosen based on the fact that it is the most widely used treatment for rhinosinusitis and it is efficacious against the most probable infecting pathogens, including Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.16 Further, a previous study13 showed that ACP was effective for treatment in this setting. To increase the likelihood of bacterial eradication, ACP 875 mg, twice daily, was given for 21 days rather than the generally prescribed 10 to 14 days. Concurrent medications that would have interfered with the evaluations were not allowed, including any form of corticosteroids, nasal decongestants, or antihistamines. Patient adherence to therapy was confirmed by weighing the nasal spray dosing containers without the patient’s knowledge. Patients were instructed to evaluate their symptoms for the previous 12 hours in a diary twice daily (AM and PM). Patients also recorded their use of study medication, other medications, and any adverse events that they experienced. Patient diaries were used for the entire 21 days of treatment. Day 21 included an overall evaluation of rhinosinusitis by the investigator using the four-point scale described previously for use by patients and investigators on day 1 and evaluation by the patients of the therapeutic response accord-
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ing to the following scale: 1 ⫽ complete relief (virtually no symptoms present); 2 ⫽ marked relief (symptoms greatly improved but scarcely troublesome); 3 ⫽ moderate relief (symptoms present and possibly troublesome but noticeably improved); 4 ⫽ slight relief (symptoms present and improved only minimally); and 5 ⫽ no relief (symptoms unchanged or worse than at baseline). Included in the evaluation of safety was an evaluation of potential changes in HPA axis function in patients from 18 treatment centers. On days 1 and 21, plasma cortisol concentrations were determined in blood samples drawn at 8:00 AM (⫾ 1 hour), before adrenal stimulation with an intravenous injection of 0.25 mg cosyntropin. Postcosyntropin plasma cortisol concentrations were determined 30 minutes after the injection. CT scans of the paranasal sinuses were made at baseline (day 1) and at day 21 and evaluated by an independent radiologist who was blinded to the treatment assignment of the patient and temporal order of the scans. Each sinus (frontal, maxillary, posterior ethmoid, and sphenoid) was scored on the level of opacity, which takes into account mucosal thickening and air/fluid level: up to 25% opacification was given a score ⫽ 0, and more than 25% opacification was given a score ⫽ 1. The frontal recess, middle meatus, and infundibulum were rated as 0 ⫽ patent and 1 ⫽ obstructed; agger nasi cell, ethmoid bulla, and sinus lateralis were rated as 0 ⫽ nonopacified and 1 ⫽ opacified. The total score was then defined as the sum of the individual scores (range 0 to 10). Note that a total score of zero does not imply that no sinus abnormality was present, as it still allows for up to 25% opacification of any of the frontal, maxillary, posterior ethmoid, or sphenoid sinuses. In addition to this scoring, the frontal, maxillary, posterior ethmoid, and sphenoid sinuses were separately rated for opacification: 0 ⫽ up to 25%; 1 ⫽ up to 50%; 2 ⫽ up to 75%; and 3 ⫽ total opacification. This separate scoring allowed for greater weighting of the larger sinuses.
Statistical Methods The primary efficacy variable was defined as the change from baseline in mean TSS as recorded twice daily over day 1 through day 15 in the patient’s diary. Two-way analysis of variance (ANOVA) was used to extract effects attributable to treatment and center, contrasting the least-squares means of MFNS doses and placebo using a 5% significance level. Similar analyses were made for day 1 through day 21 and for individual symptom scores as secondary efficacy variables. Patients’ evaluations of their responses to treatment on day 21 and investigators’ evaluations of patient responses were also analyzed by the same ANOVA noted above. Subjective evaluation of therapeutic responses to treatment was analyzed by the 2 test. The ANOVA model described above also analyzed plasma cortisol concentration data from the cosyntropin stimulation tests. RESULTS Patient Characteristics A total of 967 patients met the initial evaluation criteria and were randomized to 1 of the 3 treatment groups: ACP with MFNS 200 g, twice daily (n ⫽ 318); ACP with MFNS 400 g, twice daily (n ⫽ 324); and ACP with placebo (n ⫽ 325). There were no clinically relevant differences in demographic characteristics among the three treatment groups, and baseline symptom data were comparable (Table 1). The final inclusion criterion was radiographic evidence of rhinosinusitis on CT scan at baseline. Because this measurement introduced a lag time, some patients were started on treatments but discontinued from the study when CT data failed to show evidence of disease. The patient subset who met the inclusion criteria had CT scan confirmation of disease, available postbaseline diary data, at least 80% compliance with study medication, and at least 7 days of treatment made up the efficacy-evaluable population of 864 (Table 1, baseline symptom scores) for primary efficacy analysis. The reasons
Table 1. Demographic and Baseline Symptomatology Data
Age (yr)* (range 8–78) Male/female (%) Weight (lb)* Baseline total symptom score* Individual symptom scores*: Congestion Facial pain Headache Purulent rhinorrhea Postnasal drip Cough
Placebo (n ⴝ 325)
MFNS 200 g, twice daily (n ⴝ 318)
MFNS 400 g, twice daily (n ⴝ 324)
38.0 39/61 174.1 11.61 (n ⫽ 290)
39.4 42/58 172.0 11.57 (n ⫽ 282)
39.8 44/56 175.4 11.61 (n ⫽ 292)
2.34 1.79 1.87 2.04 2.17 1.39
2.35 1.83 1.79 1.99 2.20 1.41
2.28 1.89 1.82 2.02 2.11 1.49
* Mean values. Note: The mean values of baseline individual symptom scores and baseline TSS are based on the efficacy-evaluable subset of patients. This subset is used for the primary efficacy analysis.
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for discontinuation or exclusion were evenly distributed among the groups. Efficacy TSSs. Figure 1 illustrates that addition of MFNS 200 g or 400 g, twice daily, to ACP treatment of acute rhinosinusitis significantly improved the mean TSS for patients averaged over the period of day 1 through day 15 compared with ACP with placebo (primary efficacy variable). The mean TSS for patients receiving MFNS 200 g, twice daily, decreased from baseline by 5.89 (50%), compared with a decrease of 5.22 (44%) in patients receiving placebo (P ⫽ 0.014). Mean TSS for patients taking MFNS 400 g, twice daily, decreased by 5.86 (51%) averaged over the period of day 1 through day 15 (P ⫽ 0.017 compared with placebo). Significant improvement in TSS was also observed over the course of the entire 21-day treatment. Averaged over the period of days 1 through 21 of treatment, MFNS 200 g, twice daily, and 400 g, twice daily, produced a decrease of 6.44 (54%) and 6.51 (56%), respectively, whereas placebo showed a decrease of 5.86 (50%; P ⫽ 0.031 and P ⫽ 0.016, respectively, compared with placebo). Individual symptom scores. Individual symptom scores showed consistently greater improvement for patients treated with either dose of MFNS during treatment with ACP compared with placebo. Symptoms associated with inflammatory swelling, such as stuffiness and facial pain, were particularly better relieved by MFNS (Fig 2). The reduction in scores for stuffiness/congestion was significantly greater for patients treated with MFNS 200 g, twice daily, or 400 g, twice daily, averaged over the period of days 1 through 15 compared with placebo (P ⫽ 0.01 and P ⫽ 0.025, respectively). In addition, MFNS 400 g, twice daily, gave significantly greater relief of facial pain compared with placebo (P ⫽ 0.008). Further, Figure 2 shows added reduction of secretory symptoms, including postnasal drip, with MFNS 200 g, twice daily (P ⫽ 0.038 vs placebo) and rhinorrhea with MFNS 400 g, twice daily (P ⫽ 0.045 vs placebo). Relief of cough and sinus headache was comparable for all treatment groups (Fig 2).
Figure 1. Improvement in TSSs averaged over days 1 through 15, and days 1 through 21 of treatment. bid, twice daily.
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Figure 2. Improvement in individual symptom scores for inflammatory symptoms (congestion, facial pain/pressure/tenderness, and sinus headache) and secretory symptoms (purulent rhinorrhea, postnasal drip, and cough) averaged over days 1 through 15 of treatment. bid, twice daily.
Day 21 evaluations of response to treatment. Physician evaluations of symptoms of rhinosinusitis at day 21 were generally consistent with the averaged patient-recorded evaluations reported above. The physician evaluations found significant improvement in scores for stuffiness/congestion for patients receiving MFNS 200 g, twice daily (62%), or MFNS 400 g, twice daily (64%), compared with placebo (50%; P ⫽ 0.001 and P ⫽ 0.008, respectively). Adjunctive MFNS 400 g, twice daily, was also associated with greater reduction in the symptom score for purulent rhinorrhea (81% vs 72% for placebo; P ⫽ 0.015) and facial pain/pressure/ tenderness (74% vs 68% for placebo; P ⫽ 0.039). Patient evaluations of overall response to treatment at day 21 showed that MFNS 200 g or 400 g, twice daily, with ACP was significantly more effective than placebo with ACP (P ⱕ 0.005). Complete or marked relief was reported by 63% and 66% of patients treated with MFNS 200 g or 400 g, twice daily, respectively, compared with 55% in patients treated with placebo. Finally, physicians’ evaluation of their patients’ overall condition of rhinosinusitis showed that the addition of MFNS 200 g, twice daily, or 400 g, twice daily, to antibiotic therapy improved (reduced) the scores of the overall rhinosinusitis condition by 60% and 61%, respectively, compared with a reduction of 53% with placebo (P ⱕ 0.006). Onset of relief. Day-by-day analysis showed significant improvements of TSSs over placebo treatment as early as day 4 for patients receiving MFNS 200 g or 400 g, twice daily, as adjunctive therapy, indicating a rapid onset of relief (Fig 3A). Relief of individual symptoms showed a similar pattern. For example, the inflammatory symptom of stuffiness/congestion was significantly improved over placebo for patients receiving MFNS 200 g or 400 g, twice daily, as early as day 4 (Fig 3B).
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Figure 3. (A) Improvement in daily TSSs during days 1 through 15 of treatment. (B) Improvement in daily congestion scores during days 1 through 15 of treatment. bid, twice daily.
Evaluation of changes in CT scans of sinuses. Complete data on all 10 anatomical sites for scoring CT scans were available for 563 patients. At day 21, greater proportions of patients in the MFNS 200 g and 400 g, twice daily, treatment groups had total scores ⫽ 0 (34% and 34.5%, respectively) compared with the placebo group (29.6%). However, the mean change in score from baseline to day 21 did not differ statistically significantly among the three treatment groups. Evaluation of Safety Adverse events. Treatment with MFNS 200 g or 400 g, twice daily, and ACP 875 mg, twice daily, for 21 days was well tolerated, and most adverse events that were reported were of mild or moderate intensity. The incidence of treatment-related adverse events was similar for all three treatment groups: 12% for ACP and MFNS 200 g, twice daily, 15% for ACP and MFNS 400 g, twice daily, and 15% for ACP and placebo. The most frequently reported adverse event considered related to treatment was epistaxis (Table 2). Other local adverse events, including nasal burning, nasal irritation, and headache, occurred in ⱕ2% of patients in any treatment group. Fifty patients discontinued treatment because of adverse events, most commonly diarrhea and nausea because of ACP. These patients were equally distributed among the three treatment groups. Epistaxis, nasal irritation, nasal burning, or infection were not a cause of discontinuation for any patient. No clinically meaningful changes in mean values for clinical laboTable 2. Treatment-Related Adverse Events Occurring in ⱖ2% of Patients
Epistaxis* Nasal burning Nasal irritation Headache
Placebo (n ⴝ 325)
MFNS 200 g, twice daily (n ⴝ 318)
MFNS 400 g, twice daily (n ⴝ 324)
6% 2% 0 2%
5% 1% ⬍1% 2%
6% 1% 2% 1%
* Epistaxis included mild events, such as blood-tinged mucus or crusting/bleeding.
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ratory determinations were found, and no clinically significant abnormal laboratory values were noted for any subject. Cosyntropin stimulation test results. At 18 study sites the response to cosyntropin stimulation was analyzed as the difference between poststimulation and prestimulation plasma cortisol concentrations. Measurements made at baseline and on day 21 found no clinically relevant decreases in mean basal or stimulated plasma cortisol levels in any treatment group. No statistically significant differences were observed between groups in prestimulation and poststimulation cortisol values (Table 3). DISCUSSION Recent practice guidelines for the diagnosis and management of rhinosinusitis suggest considering the use of an intranasal corticosteroid as adjunctive therapy.5 Two essential components of rhinosinusitis management are the eradication of bacterial pathogens and the inhibition of the inflammatory process. Treatment of rhinosinusitis with standard antibiotic therapy eliminates the bacterial infection, whereas adjunctive use of an intranasal corticosteroid, such as MFNS, locally inhibits the inflammatory process.7,8,17,18 However, until recently, only a few studies have evaluated the effectiveness of the addition of an intranasal corticosteroid to standard antibiotic therapy. In a recent report of more than 400 patients with recurrent rhinosinusitis, adjunctive therapy with MFNS 400 g, twice daily, was effective in relieving rhinosinusitis symptoms, particularly those related to inflammatory swelling (ie, congestion, facial pain, and headache) compared with the antibiotic ACP with placebo.14 Recurrent rhinosinusitis may involve an underlying chronic inflammation with attendant worsening during acute episodes. Compared with ACP/placebo, the additional relief of symptoms of recurrent rhinosinusitis provided by the use of adjunctive MFNS seemed to develop over 6 to 7 days.14 Thus, the relief of recurrent rhinosinusitis by adjunctive MFNS may develop more slowly than relief of acute rhinosinusitis. The population for the current study was selected solely on the basis of presentation with acute rhinosinusitis, in contrast to the earlier study of adjunctive MFNS in patients with a history of recurrent acute rhinosinusitis. However, in both
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Table 3. Mean Concentrations of Morning Plasma Cortisol Before and After Cosyntropin Stimulation, at Baseline, and After 21 Days of Treatment MFNS 200 g, twice daily (n ⴝ 72)
Placebo (n ⴝ 75)
Prestimulation Poststimulation Poststimulation minus prestimulation
Baseline g/dL
Day 21 g/dL
Baseline g/dL
Day 21 g/dL
Baseline g/dL
Day 21 g/dL
15.9 29.9 14.0
15.6 29.8 14.2
15.4 29.8 14.4
14.3 27.5 13.3
15.4 30.0 14.6
14.8 28.6 13.8
studies, patients were required to have a CT scan reflective of rhinosinusitis. The present study of more than 900 patients with moderate symptoms of acute rhinosinusitis shows that the addition of either MFNS 200 g or 400 g, twice daily, to standard antibiotic therapy also provides significantly greater relief of symptoms, particularly stuffiness/congestion and facial pain, than antibiotic with placebo. Further, the greater relief of rhinosinusitis symptoms afforded by either dosage of MFNS adjunctive therapy was seen as by day 4 of treatment, indicating that MFNS in combination with ACP provided faster relief of rhinosinusitis symptoms compared with ACP/placebo treatment. Although no statistically significant differences in the efficacy of the two MFNS doses were detected, significant improvements in symptom scores were more consistently reported with MFNS 400 g, twice daily, than with MFNS 200 g, twice daily. Adjunctive MFNS 400 g, twice daily, provided rapid onset of relief of the symptom of congestion and stuffiness. This relief was also reflected in the time-averaged scores, both during the early phase of treatment (days 1 through 15) and throughout the entire 21-day course of treatment. Such data indicate the importance of the anti-inflammatory action of MFNS in treating the acute rhinosinusitis. Despite the improvements in symptoms with MFNS treatment, radiologic evaluation showed no statistically significant differences in CT scan images among treatment groups. Thus, in these patients radiologic evidence of underlying inflammation may persist beyond resolution of symptoms of rhinosinusitis. Both dosages of MFNS, 200 g and 400 g, twice daily, were well tolerated. Plasma cortisol responses to cosyntropin stimulation further indicated that 21-day treatment with MFNS 200 g or 400 g, twice daily, had no suppressive effect on the HPA axis. These findings are consistent with the data from clinical trials of the treatment of allergic rhinitis, which have already demonstrated MFNS to be effective and well tolerated at dosages of up to 200 g daily.19 –26 Further, studies of MFNS in adults and children with allergic rhinitis showed both a lack of HPA axis suppression and of childhood growth suppression and are consistent with extremely low bioavailability of mometasone furoate after intranasal administration.19,27,28 The results of this 21-day placebo-controlled study support the current clinical rationale of adding an intranasal cortico-
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MFNS 400 g, twice daily (n ⴝ 70)
steroid to antibiotic therapy of acute episodes of rhinosinusitis. In particular, the onset of relief of symptoms by MFNS with ACP was rapid and significantly faster than that observed for ACP with placebo. MFNS was effective and well tolerated at dosages of up to 400 g, twice daily, and there was no evidence of HPA axis suppression after adjunctive treatment with MFNS. ACKNOWLEDGMENTS The members of the Nasonex Sinusitis Group are as follows: Jeffrey Adelglass, MD, Research Across America, Dallas, TX; James N. Baraniuk, MD, Georgetown University Medical Center, Washington, DC; William Berger, MD, Southern California Research Center, Mission Viejo, CA; Robert Berkowitz, MD, Atlanta Allergy and Immunology Research Foundation, Atlanta, GA; David Bernstein, MD, Bernstein Clinical Research Center, Cincinnati, OH; Edwin Bronsky, MD, Intermountain Clinical Research, Salt Lake City, UT; William W. Busse, MD, University of Wisconsin Clinical Science Center, Madison, WI; Thomas B. Casale, MD, Nebraska Medical Research Institute, Papillion, NE; Christopher M. Chappel, MD, Family Practice Associates, Kissimmee, FL; B. Lauren Charous, MD, Milwaukee Medical Clinic, Milwaukee, WI; Theodore J. Chu, MD, San Jose, CA; Robert M. Cohen, MD, The Allergy & Asthma Clinical Research Center, LLC, Lawrenceville, GA; Jonathan Corren, MD, Allergy Research Foundation, Inc, Los Angeles, CA; Joseph David Diaz, MD, Allergy and Asthma Research Center, San Antonio, TX; David Dobratz, MD, IMTGI/College Park Family Care, Overland Park, KS; Albert F. Finn, MD, Allergy & Asthma Centers of Charleston, Charleston, SC; John W. Georgitis, MD, Bowman Gray School of Medicine, Winston-Salem, NC; Trevor I. Goldberg, MD, Charlotte Eye Ear Nose & Throat Associates, PA, Charlotte, NC; Marc F. Goldstein, MD, Larchmont Medical Center II, Mt. Laurel, NJ; David L. Goodman, MD, InSite Clinical Trials, Denver, CO; Gary N. Gross, MD, Pharmaceutical Research & Consulting, Inc, Dallas, TX; Jay Grossman, MD, Vivra Research Partners, Tucson, AZ; Robert E. Grubbe, MD, Anniston Medical Clinic, Anniston, AL; Frank C. Hampel, Jr, MD, Central Texas Health Research, New Braunfels, TX; David Jennings, MD, Research Memphis, Memphis, TN; Harold B. Kaiser, MD, Clinical Study Center, Allergy & Asthma Specialists, PA, Minneapolis, MN; George W. Kern, V, MD,
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Allergy, Asthma, & Clinical Immunology of Chester County, Ltd, West Chester, PA; Michael Lawrence, MD, Center for Clinical Research, Taunton, MA; Allen K. Lieberman, MD, HealthQuest Therapy and Research Institute, Austin, TX; W. R. Lumry, MD, Asthma & Allergy Research Associates, Dallas, TX; Clement A. Maccia, MD, Allergy & Asthma Care Clinical Research Center, Warren, NJ; Eli O. Meltzer, Allergy & Asthma Medical Group & Research Center, APC, San Diego, CA; S. David Miller, New England Research Center, Inc, N. Dartmouth, MA; Anjuli S. Nayak, MD, Asthma and Allergy Research Associates, Normal, IL; Nicholas Nayak, MD, Asthma and Allergy Research Associates, Normal, IL; Michael J. Noonan, MD, Allergy Associates Research Center, Portland, OR; Richard J. Perrotta, MD, Stuart, FL; Frank Picone, MD, Allergy & Asthma Consultants, PA, Tinton Falls, NJ; Warren W. Pleskow, MD, Encinitas, CA; Bruce M. Prenner, MD, Allergy Associates Medical Group, Inc, San Diego, CA; Paul H. Ratner, MD, Sylvana Research, San Antonio, TX; John G. Riehm, MD, Kentuckiana Allergy, PSC, Louisville, KY; Jeffrey B. Rosen, MD, Clinical Research of South Florida, Coral Gables, FL; Michael Rowe, MD, Michigan Respiratory Health and Research Institute, Novi, MI; Eric J. Schenkel, MD, Valley Clinical Research Center, Easton, PA; Jeffery L. Schul, MD, Virginia Allergy, Pulmonary and Asthma Research Center, Richmond, VA; Jay E. Selcow, MD, Connecticut Asthma & Allergy Center, West Hartford, CT; James M. Seltzer, MD, Health Advance Institute, Inc, San Diego, CA; Guy A. Settipane, MD, Asthma, Nasal Disease, & Allergy Research of New England, Providence, RI; Mark H. Shapiro, MD, Palomar Medical Group, Escondido, CA; Larry J. Shemen, MD, New York, NY; Tommy C. Sim, MD, Family Center for Asthma & Allergic Diseases, Friendswood, TX; Raymond G. Slavin, MD, St. Louis University School of Medicine, St. Louis, MO; C. Steven Smith, MD, SFI Research Labs Clinical Division, Louisville, KY; G. Edward Stewart, II, MD, Allergy and Asthma Care of Florida Clinical Research Division, Ocala, FL; James M. Sumerson, MD, Staffordshire Professional Center, Voorhees, NJ; Catherine M. VanKerckhove, MD, Colorado Allergy and Asthma Centers, PC, Aurora, CO; D. Robert Webb, MD, Allergy and Asthma Associates, Kirkland, WA; Michael Wein, MD, Doctor’s Clinic, Vero Beach, FL; Martha V. White, MD, Institute for Asthma and Allergy at Washington Hospital Center, Washington, DC; David L. Williams, MD, Atlantic Institute of Clinical Research, Daytona Beach, FL; Paul V. Williams, MD, ASTHMA, Inc, Mt. Vernon, WA; and John A. Winder, MD, Allergy and Asthma Research Center, Sylvania, OH. REFERENCES 1. Kaliner MA, Osguthorpe JD, Fireman P, et al. Sinusitis: bench to bedside. Current findings, future directions. J Allergy Clin Immunol 1997;99:S829 –S848. 2. Shapiro GG, Rachelefsky GS. Introduction and definition of sinusitis. J Allergy Clin Immunol 1992;90:417– 418. 3. Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures
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allergic rhinitis in an outdoor (park), acute exposure setting. Allergy Asthma Proc 1999;20:167–172. 27. Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children. Clin Ther 1997;19:1330 –1339. 28. Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics 2000;105:E22. Requests for reprints should be addressed to: Anjuli S. Nayak, MD Asthma & Allergy Research Associates, PC 1300 Franklin Avenue, #180 Normal, IL 61761 E-mail: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY