Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray

Asthma, rhinitis, other respiratory diseases Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray Eli O. Meltzer, MD,a B. Lauren Charous, MD,b William W. Busse, MD,c S. James Zinreich, MD,d Richard R. Lorber, MD,e Melvyn R. Danzig, PhD,e and the Nasonex Sinusitis Group* San Diego, Calif, Milwaukee and Madison, Wis, Baltimore, Md, and Kenilworth, NJ Background: Intranasal glucocorticoids are effective in the treatment of allergic rhinitis. Their effectiveness as an anti-inflammatory adjunct in the treatment of acute recurrent sinusitis has not been adequately established in a controlled clinical study. Objective: The purpose of this study was to test the hypothesis that intranasal corticosteroid treatment produces additional relief in the treatment of acute sinusitis with oral antibiotics. Methods: Patients who were 12 years old and older with a history of recurrent sinusitis were treated while experiencing a new episode of acute sinusitis, which was diagnosed by symptoms and confirmed by computed tomography scan of the paranasal sinuses. Patients were treated for 21 days with amoxicillin clavulanate potassium and randomized to receive concurrent mometasone furoate nasal spray (MFNS; Nasonex [400 µg, twice daily]; n = 200 patients) or placebo spray (twice daily; n = 207 patients). Symptom scores for headache, facial pain, congestion, purulent rhinorrhea, postnasal drip, and cough were recorded at baseline and throughout treatment. Results: Baseline symptom scores showed a moderate level of symptom severity comparable in both groups. Patient-recorded twice daily symptom scores showed that adjunctive treatment with MFNS caused a significantly greater decrease in total symptom score (primary efficacy variable) and in individual scores of inflammatory symptoms associated with the obstruction process (headache, congestion, and facial pain) compared with placebo. Symptoms associated with the secretory processes were improved to a lesser degree. Therapy-related local adverse events were not significantly different between groups. Conclusion: The addition of intranasal corticosteroid, MFNS 400 µg twice daily, to antibiotics significantly reduces symp-

From the aAllergy & Asthma Medical Group & Research Center, A Professional Corporation, San Diego; the bMilwaukee Medical Clinic, Advanced Healthcare, Service Corporation, Milwaukee; the cUniversity of Wisconsin Clinical Sciences Center, Madison; the dJohns Hopkins Medical Institutions, Baltimore; and the eSchering-Plough Research Institute, Kenilworth. *The members of the Nasonex Sinusitis Group are listed in the acknowledgment section. Supported by a grant from the Schering-Plough Research Institute, Kenilworth, NJ. Received for publication Dec 27, 1999; revised May 3, 2000; accepted for publication May 31, 2000. Reprint requests: Melvyn R. Danzig, PhD, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033. Copyright © 2000 by Mosby, Inc. 0091-6749/2000 $12.00 + 0 1/1/109056 doi:10.1067/mai.2000.109056

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Abbreviations used ACP: Amoxicillin clavulanate potassium CT: Computed tomography MFNS: Mometasone furoate aqueous nasal spray RAST: Radioallergosorbent test

toms of acute sinusitis compared with antibiotic treatment alone. (J Allergy Clin Immunol 2000;106:630-7.) Key words: Sinusitis, antibiotics, nasal corticosteroids, mometasone furoate, amoxicillin clavulanate potassium

The estimated prevalence of sinusitis is 15% in the United States, affecting more than 35 million patients.1-3 The incidence has increased approximately 18% in the past decade, which results in more than 11 million physician visits per year, more than 13 million antibiotic prescriptions per year, and a cost in excess of $6 billion per year.2,4,5 Clinical diagnosis is made through the appearance of a characteristic constellation of symptoms and signs: purulent nasal discharge, congestion, and cough lasting beyond the typical 7 to 10 days for a viral upper respiratory infection. Fever and facial pain may also occur. Sinusitis is defined as acute if it lasts less than 8 weeks and is usually amenable to medical therapy.6-10 Diagnosis is often confirmed by sinus imaging; the use of computed tomographic (CT) scans is gaining favor.10 Treatment is designed to eliminate infection, improve nasal and sinus ostial patency, promote drainage, and reduce inflammation.8 Nasal corticosteroids have become well established as first-line therapy for patients with moderate and severe persistent seasonal and perennial allergic rhinitis. Antecedent rhinitis is an extremely common and important predisposing factor to the development of sinusitis.2,11 For this reason, intranasal corticosteroids are frequently recommended as an adjunctive measure to reduce inflammation in sinusitis.1 There are few controlled studies that have tested the effectiveness of nasal corticosteroids in acute sinusitis. Because of the limited data, nasal corticosteroids are not currently approved by the Food and Drug Administration or other health-care authorities for the therapy of acute sinusitis. Three relatively small studies (which encom-

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passed 40 to 89 patients, different antibiotics, and different lengths of adjunctive steroid therapy [11 days to 3 months]) found significant improvements in patients’ symptoms over treatments with antibiotic and placebo.12-14 A larger study of 180 patients also reported significantly better relief of symptoms with adjunctive intranasal steroid at the end of the 3-week course of antibiotic therapy.15 The present study was designed to evaluate the efficacy and safety of a 3-week twice daily treatment with intranasal mometasone furoate 400 µg as an adjunctive treatment to antibiotics for acute episodes of sinusitis. At tested doses of 200 to 800 µg/d, mometasone furoate aqueous nasal spray (MFNS) appears to have extremely low (≤0.1%) systemic bioavailability.16 Plasma concentrations of mometasone furoate have been undetectable, and no suppression of the hypothalamic-pituitary-adrenal axis or childhood growth has been demonstrated after nasal administration.17,18 Doses of corticosteroids that are higher than those used for chronic control of allergic rhinitis are proposed to be more effective in the treatment of acute sinusitis.15 In sinusitis, the medication also has to be distributed in a less reliable manner to the sinus mucosa. Therefore, a short-term course of MFNS (400 µg twice daily) was selected for testing.

METHODS Study design This study was a 21-day randomized, double-blind, placebo-controlled trial conducted in 29 medical centers. Patients aged 12 years or older who experienced symptoms that characterized acute sinusitis episodes were evaluated for inclusion in the trial. Qualified patients had a history of sinusitis episodes separated by symptom-free periods (at least 2 sinus infections that required antibiotic treatment per year, for at least the past 2 years). There was no required duration of the current acute episode before inclusion. The medical history and physical examination included vital signs, blood pressure, electrocardiogram, blood chemistries, hematologic features, and urinalysis. Patients were excluded for active seasonal allergic rhinitis, viral upper respiratory infection, cystic fibrosis, nasal polyps visible on examination, Kartagener’s syndrome, glaucoma, a history of posterior subcapsular cataracts, expected immediate nasal or sinus surgery, or anatomic abnormalities precluding the delivery of medication. Patients who had used intranasal corticosteroids within 2 weeks, oral steroids within 4 weeks, or antibiotics within 1 week or who had a concurrent need for antibiotic therapy were also excluded. The study was approved by local institutional review boards, and written informed consent was obtained from each patient and/or guardian. At baseline (day 1), 6 symptoms were rated (purulent rhinorrhea, congestion, postnasal drip, headache, facial pain, cough) jointly by the investigator and patient on a 0 to 3 severity scale: 0, none; 1, mild; 2, moderate; 3, severe. For patients to be eligible for inclusion, the total symptom score had to be 6 or more (maximum possible, 18 points); at least 1 nasal symptom had to be moderate or greater (score, ≥2 points), and purulent rhinorrhea had to be present (score, ≥1 point). Limited coronal CT scans were read by a radiologist at each investigational site at the baseline visit and had to show evidence of sinusitis: mucosal thickening, opacification, or air/fluid levels present in 1 or more sinuses. Additional data on smoking and previous use of nasal corticosteroids were recorded. Total IgE and responses to a radioallergosorbent test (RAST) panel of common perennial and seasonal allergens were assessed but were not part of selection criteria.

After satisfying the inclusion and exclusion criteria, eligible patients were randomized to receive 21 days of treatment with amoxicillin clavulanate potassium (ACP; Augmentin, 875 mg twice daily) and concurrently either MFNS 400 µg twice daily, divided between both nostrils, or matching placebo in a 1:1 ratio. In this trial, ACP 875 mg twice daily was given for 21 days, rather than 10 to 14 days, to increase the likelihood of bacterial eradication. No concurrent medication that would have interfered with the evaluations was allowed, including any form of corticosteroids, nasal decongestants, opiates, or antihistamines. Acetaminophen was allowed. Patient compliance was confirmed by weighing dosing containers out of sight of the patient and by counting antibiotic tablets. Patients were given a diary in which to evaluate the previous 12 hours of symptoms twice daily (AM and PM). Each of the 6 symptoms evaluated at baseline was separately scored with the use of the 0 to 3 scale mentioned earlier. The AM score and PM score were averaged for each individual symptom. The total score each day was the sum of the 6 average scores and could range from a minimum of 0 to a maximum of 18 points. On day 21, each patient evaluated the overall therapeutic response to treatment on a 1 to 5 scale: 1, complete relief; 2, marked relief; 3, moderate relief; 4, slight relief; 5, no relief (treatment failure). Investigators also separately evaluated patient symptoms by the same criteria used at the baseline visit and overall sinusitis condition on a 0 (best) to 3 scale. CT readings were repeated after 21 days of treatment. All scans were also read and scored by an independent radiologist (S.J.Z.),9 who was blinded to the timing of the CT scan (baseline or followup) and to the treatment assignment. To compare changes with treatment, 10 landmarks were evaluated. For the frontal, maxillary, posterior ethmoid, and sphenoid sinuses, up to 25% opacification was given a score of 0, and more than 25% opacification was given a score of 1. The frontal recess, middle meatus, and infundibulum were rated as 0 (patent) or 1 (obstructed); agger nasi cell, ethmoid bulla, and sinus lateralis were rated as 0 (nonopacified) or 1 (opacified). The total score was then defined as the sum of the individual scores (total score range, 0 to 10 points). Note that a total score of zero still allowed for up to 25% opacification of any of the frontal, maxillary, posterior ethmoid, or sphenoid sinuses. In addition to the mentioned scoring, the frontal, maxillary, posterior ethmoid, and sphenoid sinuses were separately rated for range of opacification: 0, to 25%; 1, to 50%; 2, to 75%; 3, total opacification.

Statistical methods The primary efficacy variable was defined as the change from baseline in the mean total symptom score averaged for days 1 through 15 of treatment, analyzed by a 2-way ANOVA, extracting effects because of treatment, center, and treatment-by-center interaction. Similar analyses were made for days 16 through 21, for individual symptom scores, and for daily scores as secondary efficacy variables. Based on estimates from an earlier study by 1 of the investigators,15 a sample size of 200 per group was planned to detect a 0.84 difference in change from baseline with the use of a 2sided test (alpha, 0.05) with 80% power, assuming an SD of 3.0. Patients’ evaluations of their responses to treatment on day 21 and investigators’ evaluations of patient responses were also secondary variables. Patient evaluation of therapeutic responses to treatment was analyzed by the chi-squared test. Although several 3- to 5-mm coronal cuts of the sinus CT scans were provided for each patient, not all attributes could be scored for each patient. If any 1 of these attributes was missing (not visible on CT scan), then that patient’s total score was not used for analysis. The centrally evaluated CT scores were sums of dichotomized (0, 1) data and were non-normal, with a distribution skewed towards low values. Nonparametric analysis (Wilcoxon rank sum test) that

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FIG 1. Changes in mean total symptom scores during treatment for days 1 through 15 and days 16 through 21.

TABLE I. Demographic data Placebo

Sample size (n) Age (y; range 12-73)* Male/female (%) Weight (lb)* Duration of sinusitis (y)* Previous nasal steroid use (%) Smoking history (%) Total IgE > 100 µg/L (%) Any RAST 3,4,5,6 (%) Total symptoms* Purulent rhinorrhea* Postnasal drip* Congestion* Headache* Facial pain* Cough* *Mean

207 40.5 41/59 165.5 13 77 40 33 40 11.28 1.91 2.2 2.22 1.71 1.92 1.33

MFNS

200 40.2 31/69 168.8 14 69 37 27 36 11.36 1.86 2.12 2.29 1.78 1.92 1.39

values.

examined the treatment effect was performed on these scores, supported by a 1-way ANOVA.

RESULTS Patient Characteristics A total of 407 patients met evaluation criteria, which included 70% or more compliance in medication usage. The evaluated groups included 200 patients who received MFNS therapy and 207 who received placebo therapy. There were no clinically relevant differences between the treatment groups in demographic characteristics, and baseline symptom data were also comparable between groups (Table I).

Efficacy Fig 1 shows that the addition of MFNS to standard antibiotic therapy for acute sinusitis improved patients’ symptoms when compared with antibiotic with placebo therapy for

days 1 through 15 (P = .01). Mean total symptom scores for patients receiving MFNS 400 µg twice daily decreased by 5.87 (50.5%), compared with a decrease of 5.05 (44.4%) in patients receiving a placebo. For days 16 through 21, antibiotic with MFNS produced a decrease of 7.90 (68.1%), although antibiotic with placebo gave a 6.52 decrease (56.5%; P < .01). Analysis of subgroups of patients by history of smoking or by markers for atopy did not reveal differences in responses to therapy (Table II). The MFNS group in each subset improved to a greater degree. Individual symptom scores showed consistently greater improvement for patients treated with MFNS compared with placebo treatment, although relief of individual symptoms varied. Congestion and facial pain were significantly better relieved by MFNS than placebo during the early period (days 1 through 15; both groups, P ≤ .01; Fig 2, A); and all 3 inflammatory symptoms associated with swelling (headache, congestion, and facial pain) were significantly better relieved by MFNS than placebo during days 16 through 21 (each, P < .01). Of the 3 inflammatory symptoms associated with secretory processes (purulent rhinorrhea, postnasal drip, and cough), only purulent rhinorrhea was significantly improved by MFNS compared with placebo for days 16 through 21 (P ≤ .05), although there was greater reduction from baseline in the MFNS group. The change in purulent rhinorrhea did not reach statistically significant improvement during the earlier period (days 1 through 15; Fig 2, B). Comparison of daily total symptom scores showed that adjunctive MFNS produced increasingly greater relief with time than placebo (Fig 3, A). By day 7, MFNS showed greater relief (P < .05) and continued to improve more than placebo with time. Similar patterns of relief for days 1 through 15 were seen for the individual symptoms of stuffiness/congestion (P < .03, starting on day 6; Fig 3, B) and facial pain/tenderness (P < .04, starting on day 5). MFNS gave greater relief of headache symptoms on days 5 and 6 (P < .05) and marginally better relief on day 7 (P = .063), with a nonsignificant trend toward greater relief on days 8

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Meltzer et al 633

FIG 2. Changes in mean individual symptom scores during treatment for days 1 through 15 and days 16 through 21. A, Changes in symptom scores for congestion, facial pain, and headache during treatment. B, Changes in symptom scores for purulent rhinorrhea, postnasal drip, and cough during treatment.

through 15. The secretory symptoms did not show significantly better relief in daily symptom scores, although the trend indicated better relief with MFNS treatment. For the full treatment period (days 1 through 21), total symptom scores (Fig 4, A) and the individual symptom scores (Fig 4, B and C) showed patterns of greater improvement for patients treated with MFNS compared with placebo treatment similar to those observed for the 2 time periods (days 1 through 15 and days 16 through 21; Fig 2). Congestion, facial pain, and headache were significantly better relieved by MFNS than placebo (P ≤ .05), and the 3 symptoms associated with secretory processes

(purulent rhinorrhea, postnasal drip, and cough) were not significantly improved for the patients who were treated with MFNS compared with placebo treatment. Physician evaluations at day 21 showed a 68% reduction in symptoms with MFNS compared with 61% with placebo (P < .01). By their own evaluations at day 21, 62% of patients who were treated with MFNS reported complete or marked relief compared with 49% of those who had received placebo (P < .05). Of the group that received placebo treatment, 23% reported only slight or no relief of symptoms; only 12% of the group who were treated with MFNS felt slight or no symptom relief.

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FIG 3. Onset of additional relief of symptoms with MFNS during days 1 through 15. A, Daily change in mean total symptom score for days 1 through 15. B, Daily change in mean stuffiness/congestion symptom score for days 1 through 15.

CT scans All enrolled patients were required to show evidence of sinusitis in CT scans at baseline. The treatment groups were comparable with respect to the types of abnormalities noted, most commonly, mucosal thickening (noted in about 85% of patients). By day 21, CT scan readings by local radiologists were normal in 17% of patients treated with MFNS compared with 14% of patients treated with placebo (Table III). When day 21 CT scans were read by the central radiologist and scored as described earlier, a greater proportion of patients who were treated with MFNS had a total score of zero (49%), compared with the patients treated with placebo (30%). The mean change in score from baseline to day 21 was –1.8 for MFNS, compared with a mean change from baseline of –1.09 for placebo; howev-

er, this change did not reach statistical significance (Wilcoxon test, P = .09). Results for the individual attributes evaluated by the central radiologist are given in Table III. Many patients in both treatment groups showed no change in individual CT attribute scores from baseline to day 21. However, larger proportions of patients in the MFNS-treatment group showed improvements at day 21 than in the placebo group. This difference is largest for the middle meatus, infundibulum, and sinus lateralis attributes.

Safety Treatment with MFNS 400 µg twice daily and ACP 875 mg twice daily was well tolerated; most adverse events that were reported were of mild or moderate intensity. Treatment-related adverse events were reported at similar incidences between treatment groups (MFNS,

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FIG 4. Changes in symptom scores during treatment for days 1 through 21. A, Changes in mean total symptom scores during treatment. B, Changes in mean symptom scores for congestion, facial pain, and headache during treatment. C, Changes in mean symptom scores for purulent rhinorrhea, postnasal drip, and cough during treatment.

12%; placebo, 13%), and all such events were reported infrequently. The most frequently reported adverse event judged by individual investigators as possibly related to treatment was headache (MFNS, 2%, vs placebo, 3%). Similar proportions of patients who received MFNS treatment compared with patients who received placebo treatment reported local adverse events (Table IV). Eighteen patients (9 receiving MFNS [4%] and 9 receiving placebo [3%]) discontinued treatment because of adverse events, the most common being diarrhea. No clinically meaningful changes were observed in any laboratory values or in physical examinations in either MFNS or placebo group.

TABLE II. Percent improvements in total symptom scores (days 1 through 21) among subgroups

DISCUSSION

*In

Our objective was to test the hypothesis that intranasal corticosteroids produce additional relief in the treatment of acute sinusitis. Patients were enrolled with at least moderate levels of symptom severity, and patient-recorded signs and symptoms were used as the primary evaluation parameters. The study was designed with the expectation that ACP would demonstrate an early effect in the course of treatment and that the anti-inflammatory effect of MFNS would show up slightly later in the course of treatment. Thus an average of the symptom scores of the first 15 days was chosen as the primary efficacy variable. Indeed, the time-averaged total symptom scores of days 1 through 15 and days 16 through 21 show that adjunctive MFNS did provide significantly better relief even compared with aggressive 21-day antibiotic treatment and placebo. MFNS significantly relieved some individual symptoms beginning at day 6. The images of patients’ sinuses and passages were slow to improve and did not show signifi-

cant differences between patients treated with MFNS and patients treated with placebo at 21 days. Imaging scores did show a trend that MFNS therapy produced greater normalization of these structures. Inflammation, symptoms, and visible imaging abnormalities are known to heal slowly during therapy of rhinitis or sinusitis.15 Glucocorticoids modulate the humoral and cellular mechanisms involved in the inflammatory response by regulating the transcription of the genes involved in the inflammatory process.19,20 Inflammatory symptoms related to swelling (ie, congestion, headache, and facial pain) responded significantly better to MFNS treatment than to placebo treatment, although the symptoms primarily caused by secretion, rhinorrhea, postnasal drip, and cough were generally less responsive. Swelling relief could, in part, reflect a vasoconstrictor effect of mometasone furoate. There was no evidence of responder subsets; those patients with and without allergic sensitization and those patients with and without a history of

Placebo

Total IgE ≤100 µg/L >100 µg/L RAST Max value, 0-2* Max value, 3-6* Smoking No Yes

MFNS

%

n

%

n

49.6 47.4

135 67

58.0 51.2

143 53

48.1 50.0

120 83

56.8 54.9

127 72

51.9 44.2

124 83

54.9 58.2

126 74

any of the RAST tests.

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TABLE III. Percent of patients with evidence of improvements on CT scans at day 21 Placebo*‡ (%)

Local radiologist: normal at day 21 14 Central radiologist: total score, 0 at day 21 30 Frontal sinus§ 9 Maxillary sinus§ 22 Posterior ethmoid sinus§ 15 Sphenoid sinus§ 9 Frontal recess 22 Middle meatus 21 Infundibulum 16 Agger nasi cell¶ 22 Ethmoid bulla¶ 22 Sinus lateralis¶ 17 Change in total score at day 21# –1.09**

MFNS†‡ (%)

17 49 9 24 19 11 21 26 28 21 22 26 –1.77

*n = 207 patients. †n = 200 patients. ‡Values vary by item because not all items could be evaluated for every patient. §Defined as a change in score category of at least 1 unit from baseline. Defined as a change from obstructed to patent. ¶Defined as a change from opacified to nonopacified. #All data were dichotomized (ie, for > 25%, opacification score = 1). **Wilcoxon test, P = .09.

smoking improved to a greater degree with MFNS compared with patients treated with placebo. Surprisingly, patients with high RAST scores did not respond more strongly to MFNS treatment than patients with low RAST scores. Although we might anticipate that patients who have sinusitis with concomitant allergic rhinitis and an eosinophilic infiltrate would respond better to nasal corticosteroid, these factors were not determined in this study. A small percentage of patients’ headaches were listed as possibly related to therapy (MFNS, 2%; placebo, 3%); if a patient did not relate the headache to the underlying sinusitis, it was listed as an adverse event. However, there were significantly fewer sinusitis-related headaches in the MFNS group for days 16 through 21. The reported incidence of local adverse effects (such as nasal burning, stinging, and epistaxis after the administration of MFNS) was no different than in the group receiving placebo treatment. In previous studies, the adverse-event rate seen with MFNS was comparable to or lower than that with control patients receiving placebo treatment.17 In addition, a 1-year study of intranasal mometasone furoate’s topical effects demonstrated no mucosal atrophy or abnormalities of the nasal mucosa and improvement of the epithelium phenotype.21 Reducing the systemic activity of nasal corticosteroids to the lowest possible level is desirable, especially for children, postmenopausal women, elderly individuals, and individuals with asthma who are also taking inhaled or systemic corticosteroids. MFNS has a high topical potency22 and, at doses of 200 to 800 µg/d, was found to have extremely low

TABLE IV. Treatment-related adverse events that occurred in 2% or more of the patients in either treatment group Patients (%)

Headache Epistaxis Nasal burning Nasal irritation Pharyngitis

Placebo (n = 207)

MFNS (n = 200)

3 1 1 2 3

2 3 2 2 2

(<0.1%) systemic bioavailability.22 Previous clinical studies have found no drug-related systemic effects.23-26 Studies included long-term administration (≥12 months) in which sensitive indices of systemic glucocorticoid effect (eg, hypothalamic-pituitary-adrenal [HPA]-axis suppression) were used. In addition, a recent study in children showed a lack of growth suppression with 1 year of MFNS dosing.17,18 These data indicate a good safety profile for MFNS in the treatment of sinusitis. Only a few studies of smaller numbers of patients have evaluated the use of nasal corticosteroids as adjunctive therapy to antibiotics,12-15 although those studies have shown a trend toward effectiveness. In 1 of those studies, patients reported a higher overall clinical effectiveness of steroid over placebo, although only a single sign, turbinate swelling, was significantly improved over placebo treatment.15 In the current study, several individual symptom scores and the overall total showed significant improvement with adjunctive MFNS therapy over placebo therapy. The adjunctive use of MFNS in the therapy of acute sinusitis produced a more rapid and greater relief of specific individual and overall symptoms compared with placebo. MFNS was well tolerated. These results support the effectiveness of an intranasal corticosteroid as an adjunctive treatment with antibiotics for acute episodes of sinusitis, a treatment currently suggested by published guidelines.1 The members of the Nasonex Sinusitis Group are Jeffrey Adelglass, MD, Dallas, Texas; James N. Baraniuk, MD, Washington, DC; William Berger, MD, Mission Viejo, Calif; David Bernstein, MD, Cincinnati, Ohio; Edwin Bronsky, MD, Salt Lake City, Utah; William Busse, MD, Madison, Wis; Michael Wein, MD, Vero Beach, Fla; B. Lauren Charous, MD, Milwaukee, Wis; Albert F. Finn, Jr, MD, North Charleston, SC; Harold B. Kaiser, MD, Minneapolis, Minn; Clement A. Maccia, MD, Warren Township, NJ; Eli O. Meltzer, San Diego, Calif; S. David Miller, North Dartmouth, Mass; Zev Munk, MD, Houston, Texas; Robert Nathan, MD, Colorado Springs, Colo; Andrew Pedinoff, MD, Princeton, NJ; Richard Perrotta, MD, Port St Lucie, Fla; Frank Picone, MD, Tinton Falls, NJ; Warren W. Pleskow, MD, Encinitas, Calif; Bruce M. Prenner, MD, San Diego, Calif; Anthony D. Puopolo, MD, Milford, Mass; Gary Rachelefsky, MD, Los Angeles, Calif; Jeffrey B. Rosen, MD, Coral Gables, Fla; Eric J. Schenkel, MD, Easton, Pa; Guy A. Settipane, MD, Providence, RI; Raymond G. Slavin, MD, St Louis, Mo; and Suzanne Weakly, MD, Houston, Texas.

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