Endoscopic findings of polyp size and extension in nasal cavities.
Kaplan-Meier plots of time to relapse. In the intent-to-treat data set (A), median time to relapse was greater than 175 days in the group that received mometasone furoate nasal spray and 125 days in the placebo group (log-rank statistic = 3.84; P = .049). In the per-protocol data set (B), median time to relapse was 173 days in the mometasone group and 61 days in the placebo group (log-rank statistic = 7.18; P = .007).
Stjärne P, Olsson P, Ålenius M. Use of Mometasone Furoate to Prevent Polyp Relapse After Endoscopic Sinus Surgery. Arch Otolaryngol Head Neck Surg. 2009;135(3):296-302. doi:10.1001/archoto.2009.2
To evaluate the effect of mometasone furoate on prevention or reduction of nasal polyp relapse and worsening of symptoms after functional endoscopic sinus surgery (FESS).
Randomized, double-blind, placebo-controlled, multicenter study.
Ten ear, nose, and throat clinics in Sweden.
Adult subjects with bilateral nasal polyps fulfilling the criteria for surgery who underwent FESS.
Two weeks after FESS, subjects were randomized to receive mometasone furoate nasal spray, 200 μg once daily, or placebo.
Main Outcome Measures
Time to relapse, defined as an increase of 1 point or more on a 0- to 6-point endoscopic polyp scale.
In the per-protocol population (n = 104), median time to relapse was 173 and 61 days for the mometasone and placebo groups, respectively (P = .007; hazard ratio [95% confidence interval], 0.72 [0.55-0.93]). In the intent-to-treat population (n = 159), median time to relapse was greater than 175 days in the mometasone group and 125 days in the placebo group (P = .049; hazard ratio, 0.79 [0.62-0.99]). The most common adverse event was epistaxis, with 6 cases reported in the mometasone group and 3 in the placebo group.
Postoperative use of mometasone furoate, 200 μg once daily, provided a statistically significant longer time to relapse of nasal polyps than did placebo in subjects with bilateral nasal polyposis who had undergone FESS. The ability of mometasone to prevent or prolong the time to relapse among subjects undergoing FESS is important because this may prolong the time to subsequent surgery.
clinicaltrials.gov Identifier: NCT00731185
Nasal polyposis is a common inflammatory disorder of the upper airway that is estimated to affect between 2.1% and 4.3% of adults in Europe.1- 3 Although the pathophysiology of nasal polyposis is yet to be precisely defined, it involves inflammation of the sinonasal mucosa. A hallmark of bilateral nasal polyposis is a cellular infiltrate with predominant eosinophilia4 together with increased levels of inflammatory mediators, including interleukin 5 and eotaxin, which contribute to eosinophil migration and survival.5,6 The inflamed, edematous mucosa prolapses into the nasal passages and leads to the symptoms of nasal polyposis, including nasal obstruction, congestion, and impaired or absent sense of smell.7 As a result, patients experience substantial impairment of quality of life.8,9 After consideration of the underlying cause, nasal polyps are normally managed by a combination of medical and surgical interventions. Of these, corticosteroids (nasal, short-course oral) and functional endoscopic sinus surgery (FESS), a minimally invasive technique that uses an endoscope to improve ventilation and drainage, have proved to be the medical and surgical treatments of choice, respectively.10
Topical nasal corticosteroids have demonstrated substantial efficacy in small studies evaluating their use in reducing polyp size and nasal blockage in subjects with nasal polyposis.11- 15 More recently, 3 large, randomized, double-blind, placebo-controlled, multicenter trials have demonstrated that the topical corticosteroid mometasone furoate nasal spray, administered once daily, produces statistically significant reductions in nasal polyp size and congestion/obstruction score, relative to placebo, during a 4-month treatment period.16- 18 Recent guidelines from the European Position Paper on Rhinosinusitis and Nasal Polyps Group recommend intranasal corticosteroids as first-line treatment of nasal polyps in adults and provide a grade A recommendation for intranasal corticosteroid treatment in patients with nasal polyps.10 Smaller studies also have demonstrated that topical nasal corticosteroids are effective in reducing the recurrence of nasal polyps after simple polypectomy.19- 25 These benefits are, at least in part, attributable to the effect of topical corticosteroids in reducing eosinophilic infiltration of the nasal mucosa.
To date, 2 studies have evaluated the efficacy of topical nasal corticosteroids among subjects who have undergone FESS; both assessed fluticasone propionate nasal spray and produced inconsistent results, although the reasons are not clear. Hence, we have only a grade B evidence–based recommendation for treatment with nasal corticosteroids after FESS.10,26,27 The primary objective of this trial was to examine the efficacy and safety of mometasone furoate, 200 μg once daily, a topically active anti-inflammatory corticosteroid, compared with placebo, in preventing or reducing relapse of nasal polyps in subjects with endoscopically verified bilateral nasal polyposis who recently underwent FESS.
This randomized, double-blind, placebo-controlled, multicenter study was conducted at 10 ear, nose, and throat clinics in Sweden (Figure 1). After entry assessments at visit 1 (V1), qualifying subjects entered a washout phase of varying duration dependent on prestudy drugs. At V2, subjects underwent FESS, with removal of polyps, uncinectomy, and additional ethmoidal and sphenoidal exploration as indicated by clinical findings. For subjects who had previously undergone FESS, the extent of surgery depended on clinical findings, and in some cases removal of polyps was sufficient.
All subjects who gave their informed consent to participate in the study were identified by initials during V1 to V3 (follow-up). Subjects were reassessed approximately 2 weeks after surgery (baseline, V4), and those who met entry criteria were assigned a study number and randomized in a 1:1 ratio to receive either mometasone furoate, 200 μg once daily (2 sprays in each nostril), or matching placebo nasal spray, according to a computer-generated code created by a statistician (M.Å.). Randomization was performed in blocks of 4 by means of a random number generated by SAS function UNIFORM (SAS Version 6.10; SAS Institute Inc, Cary, North Carolina) and based on clock time. All participants, investigators, and staff administering the interventions and staff assessing the outcomes were blinded to group assignment. Treatment began approximately 2 weeks after surgery and continued for 24 weeks if no relapse occurred.
Subjects were also supplied with 20 pipettes containing oxymetazoline hydrochloride (0.5 mg/mL) as rescue medication. Follow-up assessments were conducted at 28, 56, 112, and 168 days after randomization to therapy, with a ±7-day window for each visit.
The final study protocol, including amendments and final versions of the subject information and consent forms, was reviewed and approved by an independent ethics committee/institutional review board and the Swedish Medical Products Agency before enrollment of subjects. All subjects gave written informed consent to participate in the study. The study was conducted in accordance with the protocol, regulatory requirements, good clinical practice, and the ethical principles of the Declaration of Helsinki, as adopted by the World Medical Assembly, 1964 (and subsequent revisions).
At study entry, subjects were required to be 18 years or older with bilateral nasal polyps fulfilling the criteria for surgery. Asthmatic subjects could be included if they had not had an exacerbation of their asthma within 30 days before consideration for entry. If treated with inhaled corticosteroids, these subjects were required to be on a moderate, stable-dose regimen of beclomethasone dipropionate, 1000 μg/d or less, or the equivalent.
Subjects were excluded from the study if they had had a polypectomy within the previous 6 months; unhealed nasal surgery or trauma; more than 5 previous polypectomies; or ongoing concurrent nasal infection, rhinitis medicamentosa, hereditary mucociliary dysfunction, nasal structural abnormalities, or an idiosyncratic reaction to corticosteroids. Subjects were also excluded if they had active or latent pulmonary tuberculosis; other significant medical conditions that, in the investigators' judgment, could interfere with evaluations (eg, cystic fibrosis); or a history of hypersensitivity to the study medication, or if they were pregnant, lactating, or not using an adequate prophylactic measure. Intolerance of nonsteroidal anti-inflammatory drugs was not an exclusion criterion.
At baseline, subjects were required to have had functional endoscopic sinus surgery according to the prespecified surgical procedure and had a polyp score of 1 or less (sum of score from both nostrils). Asthmatic subjects could be included if they had not had an exacerbation of their asthma since V1. Asthmatic subjects receiving treatment were required to be receiving a moderate, stable dose of inhaled corticosteroids, not exceeding a beclomethasone dosage of 1000 μg/d or the equivalent. Baseline exclusion criteria were similar to those for study entry.
Washout periods of varying durations were required for subjects who were taking additional medications at study entry. Required washout periods were 3 months for intramuscular or intra-articular corticosteroids; 4 weeks for inhaled (unless taking a stable dosage for treatment of asthma), oral, intravenous, rectal, intranasal, or ocular corticosteroids; 30 days for investigational drugs; 2 weeks for certain high-potency dermatologic agents; 1 week for nasal atropine and ipratropium bromide; 5 days for hydroxyzine hydrochloride; 72 hours for long-acting antihistamines and oral decongestants; and 24 hours for short-acting antihistamines and oral, nasal, and ocular decongestants.
Treatments prohibited during the study period included systemic corticosteroids, inhaled corticosteroids (other than beclomethasone dipropionate, ≤1000 μg/d or the equivalent for the treatment of asthma); high-potency dermatologic corticosteroids (unless taking a stable dosage for the treatment of chronic dermatologic disorders); topical nasal corticosteroids other than the study drug; topical ocular corticosteroids; topical nasal or ocular antihistamines; nasal atropine or ipratropium; oral decongestants; nasal decongestants other than the supplied rescue medication; antileukotrienes; devices that dilate the nostrils to improve nasal breathing; and nasal isotonic sodium chloride solution (after baseline).
Endoscopy of the nasal cavity, after decongestant use, was performed at all study visits. The polyp score was graded for each nasal cavity on a scale of 0 to 3 (0, no polyps; 1, polyps in the middle meatus, not reaching below the inferior border of the middle turbinate; 2, polyps reaching below the inferior border of the middle turbinate but not the inferior border of the inferior turbinate; and 3, large polyps reaching to or below the inferior border of the inferior turbinate or polyps medial to the middle turbinate). Polyp size and extension were drawn on a diagram representing the coronal (Figure 2) and sagittal views. Peak nasal inspiratory flow was performed before decongestant administration at V4 to V8. A butanol olfactory threshold test was also performed before decongestant administration at V4, V6, and V8. Signs and symptoms of nasal polyposis were recorded once each day by the subject in a diary, and at each visit the subject and investigator performed a joint evaluation. Severity of nasal stuffiness/congestion, rhinorrhea, and sense of smell were individually scored on a scale of 0 to 3, ranging from no signs/symptoms or normal sense of smell (0 points) to severe symptoms or complete lack of sense of smell (3 points). Adherence to study treatment was recorded by patients on a daily basis in a diary. Adverse events (AEs) were collected and reported from V2 (surgery) through the end of the study.
All subjects who had received 1 or more doses of the study drug were included in the safety population. The intent-to-treat (ITT) population included all subjects who received 1 or more doses of the study medication and had baseline and postbaseline data. The per-protocol (PP) population included all subjects who met inclusion/exclusion criteria, took the study medication as specified in the protocol, and did not take a prohibited concomitant medication during the study.
At a sample size of 62 subjects per treatment arm, a .05-level 2-sided log-rank test for equality of survival curves was estimated to have 80% power to detect the difference between a group 1 proportion of 0.65 and a group 2 proportion of 0.40 (a constant hazard ratio of 0.46). With an estimated fraction of 15% of subjects with nonevaluable data, it was estimated that 146 subjects needed to be included in the trial.
The primary end point was the time to relapse from baseline, with relapse defined as an increase in polyp score of 1 or more, in which baseline scores were 1 or less. The score was recorded as the sum of scores from both nostrils. Secondary end points included subjective symptoms, butanol olfactory threshold, and peak nasal inspiratory flow.
Kaplan-Meier curves were generated for the time to relapse, and the 2 groups were compared by a log-rank test. Subjects who terminated the study prematurely and had a relapse recorded at the time of dropout or withdrawal were included in the analysis as relapse; subjects who ended the study without having a relapse were included in the analysis as censored observations. Hazard ratios were estimated by the Cox proportional hazards model. Binary variables were compared by the Mantel-Haenszel χ2 test, stratified by center. Treatment × center interaction was tested by applying the Breslow-Day test of homogeneity of the common odds ratio. Continuous and ordinal variables were compared by Wilcoxon rank sum tests.
A total of 201 subjects were screened, of whom 162 were randomized to treatment. Of these, 80 were randomized to the study drug and 82 were randomized to placebo. Visit 1 was conducted from September 2, 2003, to March 8, 2005; the date for the last subject out was September 14, 2005. Most baseline characteristics were similar in each group (Table 1).
All 162 subjects were included in the safety analysis; 159 subjects had postbaseline efficacy data and were included in the ITT data set. A total of 104 subjects met all criteria for the PP analysis (Table 2). Eighty subjects in the ITT population (50.3%) completed the study, including 43 (54%) in the mometasone group and 37 (46%) in the placebo group; corresponding numbers in the PP population were 32 (60%) and 20 (39%), respectively. Reasons for early termination are given in Table 2.
The results for the primary efficacy variable (time to relapse) are shown in Figure 3. The relapse-free period was significantly longer among subjects who received mometasone in both the ITT and PP datasets. For the PP analysis, the median time to relapse was 173 days in the mometasone group and 61 days in the placebo group (P = .007; hazard ratio and 95% confidence interval [CI], 0.72 [0.55-0.93]). Median time to relapse in the ITT population was greater than 175 days in the mometasone group and 125 days in the placebo group (P = .049; hazard ratio and 95% CI, 0.79 [0.62-0.99]).
The proportion of subjects in the ITT data set with moderate to severe symptoms of nasal stuffiness/congestion was 84.3% (134 patients) before surgery, 15.1% (24 patients) at randomization (V4), and 10.1% (16 patients) at the end of treatment. The pattern was similar for most secondary efficacy variables. Change from baseline to end of treatment in scores for nasal stuffiness/congestion and subjective sense of smell (as evaluated jointly by physician and patient) did not demonstrate significant differences between the mometasone and placebo groups (Table 3). Change from baseline to end of treatment demonstrated significantly better outcomes for rhinorrhea in these evaluations among subjects who received mometasone compared with placebo (P = .004 for the ITT population; odds ratio [95% CI] for improvement rates, 0.14 [0.03-0.53]). Similarly, although diary symptom scores showed no significant difference between the 2 groups for nasal congestion or sense of smell, significantly better scores for the rhinorrhea component were observed in the ITT data set of the mometasone group (P = .04; mean difference [95% CI], 0.15 [0.01-0.30]). There were no significant differences between the 2 groups in changes in peak nasal inspiratory flow, which is likely explained by the marked improvement in nasal blockage after surgery. Regarding the butanol threshold tests, there was no deterioration over time and there were no significant differences between the 2 treatment arms.
Observed treatment effects were homogeneous across study centers. In complementary analyses, poststratification with respect to a history of allergic rhinitis or asthma was performed. The results of the stratified analyses were consistent with the main treatment comparisons. In the placebo-treated group (PP), the median time to relapse was 48 days among subjects with a history of allergic rhinitis compared with 110 days in subjects without a history of allergic rhinitis (P = .03; hazard ratio [95% CI], 0.58 [0.33-0.94]). Among the subjects with a history of asthma, in the same group, median time to relapse was 48 days compared with 72 days in subjects with out asthma (P = .04; hazard ratio [95% CI], 0.42 [0.16-0.86]). In the mometasone group, no major differences were seen between the corresponding subgroups.
The frequency of AEs with mometasone and placebo was comparable. Of the 162 subjects included in the safety analysis, a total of 75 and 59 surgery-related AEs occurred in the mometasone and placebo groups, respectively. Excluding AEs related to surgery, 101 AEs (primarily mild to moderate) were reported in the mometasone group and 106 in the placebo group during the treatment period. A total of 7 AEs, including 3 in the mometasone group and 4 in the placebo group, led to discontinuation during the treatment period. One of these in the mometasone group was reported as a serious AE related to surgery (nasal bleeding). In the mometasone group, 11 treatment-related AEs were reported, including 6 cases of epistaxis (which included a broad range of bleeding episodes from frank bleeding to bloody nasal discharge to flecks of blood in the mucus), 2 cases of dyspepsia, and 1 case each of obstruction, headache, and sneezing. In the placebo group, 9 events were reported as treatment related, including 3 cases of epistaxis and 1 case each of nausea, headache, nasal congestion, rhinorrhea, sneezing, and skin irritation.
In the present study of postsurgical subjects who underwent FESS, treatment with mometasone furoate nasal spray, 200 μg once daily, resulted in a significantly longer relapse-free period than placebo. Overall, mometasone was well tolerated, with most AEs classified as mild.
With the exception of rhinorrhea (as measured by both physician and subject), there were no differences between the 2 groups on secondary outcomes. This lack of effect on most secondary outcome measures is unsurprising, as it is most likely related to the effect of FESS, eg, the major impact of FESS on many signs and symptoms of nasal polyposis gave little room for additional improvement and thus may have obscured differences between mometasone and placebo on these measures. In an earlier clinical study, FESS significantly reduced nasal obstruction due to nasal polyposis even after a previous combined oral and intranasal corticosteroid treatment.28 In complementary stratified analyses, we found that subjects in the placebo group (PP analysis) with a history of allergic rhinitis or asthma had a shorter time to polyp relapse than did subjects without allergic rhinitis or asthma. This may point to a more aggressive inflammatory disease in patients with allergic rhinitis or asthma and nasal polyposis, suggesting that presence of allergic rhinitis or asthma negatively affects the postoperative outcome. Physicians should check for allergic rhinitis and asthma in patients with nasal polyposis, since a subgroup of patients fits this profile.
Previous studies have found that other intranasal corticosteroids, including beclomethasone, budesonide, and flunisolide, are effective in reducing the recurrence of nasal polyps after simple surgery.19,21- 25 However, these studies were limited in that most of them enrolled a small number of subjects and the surgery performed was primarily simple polypectomy.
Dijkstra and colleagues27 evaluated fluticasone propionate aqueous nasal spray for the prevention of chronic rhinosinusitis and nasal polyps among subjects undergoing FESS. In a double-blind, placebo-controlled study, the investigators randomly assigned adults who had undergone FESS (N = 162, but only 68 with nasal polyps) to receive fluticasone propionate, 400 μg twice daily, 800 μg twice daily, or placebo for 1 year. The primary end point was the percentage of subjects who were withdrawn from the trial because of recurrent or persistent disease, defined as progressive regrowth of nasal polyps, recurrent signs and symptoms of chronic sinusitis combined with signs of rhinosinusitis at nasal endoscopy, and abnormalities on computed tomographic scan, or persistent complaints for 2 months or more after FESS. A significant reduction in symptoms was seen after FESS; however, after 1 year, there were no significant differences between the fluticasone propionate groups (400 and 800 μg) and the placebo group in the percentage of subjects who withdrew because of recurrent or persistent disease (51%, 55%, and 39%, respectively). Compared with placebo, recurrence rates were 1.22-fold higher in the 400-μg group and 1.48-fold higher in the 800-μg group. Similarly, when subjects with a high polyp score during FESS were analyzed separately, there remained no significant difference between fluticasone and placebo.
Another long-term, prospective, randomized, stratified, double-blind, placebo-controlled study assessed 109 subjects with chronic rhinosinusitis—including 77 subjects with polyposis—who underwent FESS and were randomly assigned 6 weeks after surgery to therapy with fluticasone propionate, 200 μg twice daily, or placebo.26 At 5 years, changes in a visual analog scale measuring how subjects felt overall were significantly better among subjects who received fluticasone than those who received placebo. Changes in endoscopic edema, polyp scores, and total nasal volumes also were significantly better in the fluticasone group than in the placebo group at 4 years.
The results of the present study are consistent with data from previous trials that demonstrated consistent reductions in polyp grade at 4 months in subjects with nasal polyposis who were medically treated with mometasone.16- 18 These trials led to the approval of mometasone for the treatment of nasal polyps in adults. The deterioration of symptoms after FESS in patients with nasal polyposis is hard to capture within the study period of a maximum of 6 months. Hence, the time to relapse in polyp size was chosen as the primary end point. For ethical reasons, to conduct a longer placebo-controlled study was not an option in Sweden.
Subjects with bilateral nasal polyposis who received mometasone furoate, 200 μg once daily, after FESS demonstrated a significantly longer time to relapse than did subjects who received placebo. Because patients with polyposis frequently need additional surgical procedures because of regrowth of nasal polyps and worsening of symptoms, the ability of mometasone to extend time to relapse has direct positive implications for patients and physicians, as well as the potential to reduce overall costs related to the management of this condition. In patients with nasal polyposis, when and on which patients to perform FESS are questions that remain largely unanswered.
Correspondence: Pär Stjärne, MD, PhD, Department of Clinical Sciences, Intervention and Technology, Division of Otorhinolaryngology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden (email@example.com).
Submitted for Publication: February 19, 2008; final revision received July 1, 2008; accepted July 6, 2008.
Author Contributions: Dr Stjärne had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Stjärne and Olsson contributed equally to the manuscript. Study concept and design: Stjärne. Acquisition of data: Stjärne and Olsson. Analysis and interpretation of data: Stjärne, Olsson, and Ålenius. Drafting of the manuscript: Stjärne and Olsson. Critical revision of the manuscript for important intellectual content: Stjärne, Olsson, and Ålenius. Statistical analysis: Ålenius. Obtained funding: Stjärne. Administrative, technical, and material support: Stjärne and Olsson. Study supervision: Stjärne and Olsson.
Financial Disclosure: Dr Stjärne has received honoraria from Schering-Plough and GlaxoSmithKline for educational activities and for consulting on advisory boards for Schering-Plough, GlaxoSmithKline, and Novartis.
Funding/Support: This study was supported by Schering-Plough AB. Editorial assistance provided by John R. Ferguson, PhD, was funded by Schering-Plough AB.
Previous Presentations: This study was presented as a poster at the XXVI Congress of the European Academy of Allergology and Clinical Immunology, June 9-13, 2007, Göteborg, Sweden; the annual meeting of the American Academy of Otolaryngology, Head and Neck Surgery, September 16-19, 2007, Washington, DC; and the Congreso Latinamericano de Rinologia y Cirugia Plastica Facial, November 7-10, 2007, Cuzco, Peru.
Additional Contributions: The following investigators also participated in this study: Lars Lundblad, MD, PhD, Department of Otorhinolaryngology, Karolinska University Hospital, Solna, Sweden; Mats Holmström, MD, PhD, Department of Otorhinolaryngology, Uppsala University Hospital, Uppsala, Sweden; Per-Olof Eriksson, MD, PhD, Department of Otorhinolaryngology, Norrlands University Hospital, Umeå, Sweden; Lars Olaf Cardell, MD, PhD, Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, and Karolinska University Hospital, Huddinge, Sweden; Anders Cervin, MD, PhD, Department of Otorhinolaryngology, Head and Neck Surgery, Lund University Hospital, Lund, and Helsingborg Hospital, Helsingborg, Sweden; Kjell Ydreborg, MD, Department of Otorhinolaryngology, Ryhov Hospital, Jönköping, Sweden; Bo Wilhelmsson, MD, PhD, Department of Otorhinolaryngology, Central Hospital, Västerås, Sweden; Karl Steensland, MD, Department of Otorhinolaryngology, Kalmar Hospital, Kalmar, Sweden; Leif Johansson, MD, PhD, Department of Otorhinolaryngology, Central Hospital, Skövde, Sweden; and Anna Hallberg, RN, Karolinska University Hospital, Huddinge, Sweden.