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Nasal Budesonide Offers Superior Symptom Relief in Perennial Allergic Rhinitis in Comparison to Nasal Azelastine
Nasal budesonide offers superior symptom relief in perennial allergic rhinitis in comparison to nasal azelastine Dr Martin A Stern*, FRCP, MSc (Immunol); Dr Alan G Wade, MB, ChB Glas; Dr Sally M Ridout, MRCGP; and L Malcolm Cambell, MRCGP
Background: Allergic rhinitis is usually treated with oral antihistamines or nasal steroids. Topically active nasal antihistamine is a new treatment modality for allergic rhinitis. The efficacy in comparison to well established topical treatment alternatives is not fully known. Objective: To compare the efficacy of intranasally administered azelastine to budesonide, at their respectively recommended dosage, on the symptoms of perennial rhinitis patients. Methods: A placebo-controlled, randomized, parallel group study was conducted to compare the efficacy and tolerability of intranasal budesonide aqueous suspension (256 g once daily) with azelastine hydrochloride nasal spray (280 g twice daily (560 g/day)) and with placebo in the treatment of perennial allergic rhinitis. The 195 patients (with at least a 2-year history of perennial allergic rhinitis) recorded individual nasal symptom scores, the degree of symptom control achieved and any adverse events experienced over a 2-week baseline period and a 6-week treatment period. Results: Following treatment, the reductions in mean combined and individual nasal symptom scores from baseline values were significantly greater in the budesonide group compared with the placebo group (P ⬍ .0001 for all variables except runny nose P ⫽ .01). In patients treated with budesonide, there were also significantly larger reductions from baseline values in combined nasal symptom scores (P ⬍ .01) and in scores for all individual nasal symptoms (P ⱕ .05) compared with those treated with azelastine. The reductions from baseline in both combined and individual nasal symptom scores did not differ between azelastine and placebo. The study medications were well tolerated, producing no unexpected or serious treatment-related adverse events. Conclusion: A once-daily dose of 256 g of intranasal budesonide aqueous suspension is significantly more effective at relieving the symptoms of perennial allergic rhinitis compared with a twice daily dose of 280 g of azelastine nasal spray. Ann Allergy Asthma Immunol 1998;81:354–358.
INTRODUCTION Perennial allergic rhinitis is characterized by nasal obstruction, rhinorrhea, sneezing, and nasal itching. The aller* Martin A. Stern, MD, Midlands Asthma and Allergy Research Association (MAARA), Leicester General Hospital, Leicester, United Kingdom. This study was supported by a grant from Astra Draco AB, Lund, Sweden. Received for publication October 17, 1997. Accepted for publication in revised form March 24, 1998.
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gens responsible are perennial (such as house dust mites and animal dander) and are often ubiquitous and, therefore, unavoidable. The first line of treatment is with oral antihistamines if the symptoms are mild. If the symptoms are more troublesome, topical treatment is recommended with nasal sprays or aqueous suspensions containing corticosteroids, such as budesonide. Supplementation on an ‘as needed’ basis can be provided with an oral antihistamine.1
Nasal inhalation of topically active budesonide has been shown to be effective and safe in the treatment of both perennial and seasonal allergic rhinitis.2 Delivery of budesonide from a nasal pressurized metered dose inhaler has been shown to result in retention of a proportion of the nominal dose in the nasal adapter: for example, 256 g of a nominal dose of 400 g is delivered to the patient from a nasal pressurized metered dose inhaler whereas the entire nominal dose (400 g) is delivered with an aqueous nasal spray. A recent study comparing a dose of 256 g with a dose of 400 g of budesonide aqueous suspension, each given once daily, has shown that the lower dose has a similar clinical efficacy to that of the higher dose.3 Azelastine is a second-generation histamine H1-receptor antagonist which also inhibits the release of other mediators involved in the pathogenesis of allergic disease and bronchial asthma.4,5 Azelastine (280 g twice daily) administered intranasally was found in open and uncontrolled studies to have similar efficacy to intranasal budesonide (100 g twice daily) for the treatment of patients with perennial allergic rhinitis.6 The aim of the current placebo-controlled study was to compare the efficacy of budesonide (256 g once daily) and azelastine (280 g twice daily) aqueous nasal sprays, and placebo in the treatment of patients with perennial allergic rhinitis. The primary efficacy variables were daily nasal symptom scores, evaluated from patient diaries, and the patients’ overall assessment of treatment efficacy.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
METHODS Subjects A total of 195 adult patients with at least a 2-year history of perennial allergic rhinitis, confirmed by a positive skin prick test, were recruited into the study at four centres in the UK. Preferably, patients were allergic to house dust mites, although patients allergic to cat, dog, Alternaria and Cladosporium were also accepted. In addition, the patients had to demonstrate at least one of the nasal symptoms of blocked nose, rhinorrhea, or sneezing with scores higher than or equal to 2 (moderate symptoms) on a 0 to 3 point scale on four or more days of the 2-week baseline period. Patients with septal deviation or other anatomic nasal obstructions that would prevent the effective penetration of the nasal spray were not enrolled in the trial. In addition, patients who had used topical nasal corticosteroid therapy in the previous 2 weeks, oral systemic corticosteroid therapy in the preceding 2 months, depot steroid therapy in the previous 6 months or immunotherapy for perennial allergic rhinitis in the past 2 years did not participate in the study. Pregnant women and nursing mothers were also excluded. The study was performed in accordance with the principles of the declaration of Helsinki. The protocol was approved by a regional ethics committee and signed informed consent was obtained from all patients. The study was sponsored by Astra Draco AB, Sweden. Study Design The study was a multicenter, placebocontrolled, randomized, parallel group trial and was double-blind with respect to budesonide and placebo, and investigator-blind with respect to azelastine. This was achieved by having a third person at the clinic handle all communication regarding the drugs with the patient. The patients were informed that some patients will get budesonide, some will get azelastine, and the rest will get sprays containing a dummy treatment (placebo). After a 2-week baseline period, the patients were ran-
VOLUME 81, OCTOBER, 1998
domized in a computerized scheme in balanced blocks of three to one of the treatment groups budesonide aqueous suspension (256 g once daily), azelastine aqueous suspension (280 g twice daily), or placebo (once daily) for a period of 6 weeks. Terfenadine tablets (60 mg) were used as rescue medication, if needed. Clinical Efficacy Symptom evaluation was achieved through a score system recorded in diaries. Every evening, patients assessed the severity of the individual symptoms (blocked nose, rhinorrhea, and sneezing) according to a 4-point scale: 0 ⫽ no symptoms, 1 ⫽ mild symptoms (not troublesome), 2 ⫽ moderate symptoms (troublesome, but not enough to interfere with normal daily activity or sleep), and 3 ⫽ severe symptoms (interfere with normal activity or sleep). Combined symptom scores were the sum of the scores for the three individual nasal symptoms. The mean patient scores of both individual and combined symptom severity were calculated for the 2-week baseline period and for the 6-week treatment period. In addition, patients made an overall assessment of treatment efficacy after 6 weeks of treatment according to the degree of symptom control achieved (aggravation, none, minor, substantial, or total control). The number of terfenadine tablets taken as rescue medication (a maximum of two tablets per day) was also recorded. Tolerability The incidence, severity, and nature of adverse events were determined by examining and questioning the patients after 3 and 6 weeks of treatment. A rhinoscopic examination was also performed at each visit including an evaluation of hypertrophy of the conchae, nasal polyps, pus, secretion, other structural defects or any signs of candida infection. Statistical Analysis A sample size of 50 patients in each treatment group was estimated to provide an 80% power to detect a treat-
ment difference of 0.40 in the individual symptom scores, assuming a standard deviation of 0.7. The mean symptom scores for the 2-week baseline period and the 6-week treatment period and the differences between these scores were calculated for each of the three treatment groups. The differences in individual symptom scores and mean combined nasal symptom scores between the baseline and treatment periods were based on all patients treated approach and subjected to an analysis of variance, with treatment and center as factors included in the model. Overall assessment of treatment efficacy and the difference in terfenadine use between baseline and treatment periods were also subjected to an analysis of variance. The main analysis of clinical efficacy was based on the all patients treated approach: all patients who had taken at least one dose of the study medication were included. RESULTS Patient Population A total of 195 patients (65 in each treatment group) completed the baseline assessment and entered the treatment period (Table 1). Fifty patients discontinued the study during the treatment period because of adverse events (n ⫽ 17; placebo 4, azelastine 7, budesonide 6), disease deterioration (n ⫽ 14; placebo 7, azelastine 3, budesonide 4) or other reasons (n ⫽ 19; placebo 5, azelastine 9, budesonide 5). Consequently, 145 patients completed the entire trial. The three treatment groups were comparable with respect to sex, age, weight, height, and disease duration. The majority of patients were allergic to house mites with an even distribution between the treatment groups (Table 2). The mean disease duration was 13.4 years (range: 2 to 45 years). During the baseline period, the means of the combined nasal symptom scores in the three treatment groups were 4.28 for placebo, 3.85 for azelastine, and 4.33 for the budesonide group. The individual means of the symptom scores for blocked nose were
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1.7, 1.5, and 1.6 in the placebo, azelastine and budesonide groups. For rhinorrhea the corresponding values were 1.3, 1.3, and 1.4. For sneezing the values were 1.2, 1.1, and 1.3. Clinical Efficacy A comparison of the reductions in mean combined and individual nasal symptom scores (blocked nose, rhinorrhea, and sneezing) from baseline values showed that this reduction was significantly greater in the budesonide group compared with the placebo group. There were also significantly larger changes from baseline values in combined nasal symptom scores and in individual nasal symptom scores in the budesonide group compared with the azelastine treatment group. In contrast, azelastine did not produce a significant improvement in either combined or individual nasal symptoms during the 6-week treatment period compared with placebo (Fig 1). The patients’ overall assessments of treatment efficacy after 6 weeks of therapy indicated that budesonide produced significantly superior symptom control compared with both azelastine and placebo (P ⫽ .013 and P ⫽ .0003, respectively (Fig 2). In addition, at the end of the 6-week treatment period, there was no significant difference between azelastine and placebo with respect to the degree of symptom control achieved (P ⫽ .20). A secondary efficacy variable was the use of terfenadine tablets (60 mg) as rescue medication during the baseline and treatment periods. The reduction from baseline in the weekly consumption of terfenadine was significantly greater for budesonide (⫺1.03 tablets, P ⫽ .0033) and azelastine (⫺1.61 tablets, P ⫽ .0015) compared with placebo (⫹0.06 tablets), but there were no differences between the two active treatments (P ⫽ .80; Table 3). Tolerability No unexpected or treatment-related adverse events were reported; however, 17 of the 195 patients enrolled in the study discontinued the trial because of adverse events (six in the budesonide
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Table 1. Demographic Characteristics of Patients Entering the 6-Week Treatment Period Treatment Group
Number of patients Age, years Mean Range Gender Male/female Disease duration, yr Mean Range
Placebo
Azelastine, 280 g, bid
Budesonide, 256 g, qd
All
65
65
65
195
35.3 18–60
38.2 18–73
37.2 19–68
36.9 18–73
33/32
33/32
33/32
99/96
11.8 2–39
13.5 2–45
14.8 2–40
13.4 2–45
qd ⫽ once daily and bid ⫽ twice daily. Table 2. Distribution of Different Allergens Between Treatment Groups (%) Allergen D. pteronyssinus D. farinae Dog Cat Alternaria Cladosporium
Placebo, %
Azelastine, %
Budesonide, %
Total, %
29.7 24.6 16.4 19.0 6.2 4.6
29.2 23.1 14.4 13.9 5.6 3.6
31.8 21.5 16.4 18.0 6.7 5.0
90 69 47 51 18 13
group, seven in the azelastine group and four in the placebo group). The majority of adverse events were of mild or moderate intensity and were similar between the three treatment groups. The most frequently reported adverse events were respiratory infection, headache, flu-like disorders, and epistaxis. One serious adverse event (hepatic cirrhosis) was reported in the placebo group but any causal relationship to the study medication was considered unlikely. Rhinoscopic examinations did not reveal any major abnormalities, and there were no cases of Candida infection. A clear tendency of change towards none or mild for mucosal swelling and secretion was seen in the budesonide group as compared with the other two treatment groups. DISCUSSION The present study has shown that intranasal budesonide aqueous suspension (256 g once daily) is significantly more efficacious than both placebo and azelastine nasal spray (280 g twice daily) in controlling the symptoms of perennial allergic rhini-
tis. This difference in activity between budesonide and azelastine also appeared to be clinically relevant since 70% of patients treated with budesonide reported substantial or total control over symptoms compared with only 45% and 27% of patients treated with azelastine and placebo, respectively. The distribution and severity of the individual symptoms were similar in the treatment groups. The higher consumption of rescue medication in the azelastine group might have reduced the symptom scores during baseline to a greater extent than in the budesonide treated group. The higher consumption could reflect that the azelastine group was more symptomatic and, thus, would have had more improvement to gain as a result of treatment. In the comparison the gain in the budesonide treated group was greater. Of the individual nasal symptoms, nasal blockage is the most troublesome in patients with perennial allergic rhinitis. It is, therefore, of particular interest that budesonide produced twice as large a decrease in the score for blocked nose than did azelastine.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 1. Change of individual and combined mean nasal symptom scores from baseline (AZEL ⫽ azelastine treated group, BUD ⫽ budesonide treated group).
Figure 2. Patients overall assessment of efficacy after 6 weeks of treatment. (AZEL ⫽ azelastine treated group, and BUD ⫽ budesonide treated group).
Several double-blind studies, comparing nasal budesonide with various antihistamines, in both seasonal and perennial allergic rhinitis have demonstrated budesonide to be superior.6 – 8 In contrast, a previous open trial showed that azelastine nasal spray (280 g twice daily) was more effective than a low dose of budesonide nasal pressurized metered dose inhaler (100 g twice daily) in controlling the symptoms of perennial allergic rhinitis.9 In a double-blind study, however, nasal
Table 3. Mean Weekly Consumption of As-Needed Terfenadine Tablets (60 mg) during Baseline and Treatment Periods Treatment Period
Baseline period Treatment period Difference
Placebo
Azelastine, 280 g, bid
Budesonide, 256 g, qd
2.14 2.20 ⫹0.06
2.66 1.05 ⫺1.61
1.67 0.64 ⫺1.03
VOLUME 81, OCTOBER, 1998
budesonide was demonstrated as being more efficient than astemizole given orally, in controlling the symptoms of perennial rhinitis.10 As stated in a consensus report, antihistamines have usually been taken orally (either as tablets or syrup), which has the advantage of reducing systemic symptoms such as conjunctivitis and urticaria. Unfortunately, some serious cardiac side effects have been observed with some antihistamines taken orally, but these side-effects are not due to class-effect of antihistamines. Topical antihistamines such as azelastine and levocabastine can be used for acute symptomatic relief and prophylaxis of allergic rhinitis without any systemic side effects.1 The current study was single-blind, rather than double-blind with respect to azelastine since no azelastine-placebo was available. The investigator was thereby kept unaware of the study treatment and could not influence the assessment of treatment efficacy made by the patients. Azelastine is a topical second-generation H1-receptor antagonist that has properties similar to terfenadine, loratadine, and cetirizine: it is effective at inhibiting the release of histamine and prostaglandin from mast cells and basophils. Perennial allergic rhinitis is characterized by a chronic inflammatory reaction in the nasal epithelium and submucosa involving mast cells, eosinophils, T cells, and macrophages. Although antihistamines may help to alleviate symptoms, it is doubtful to what extent they exert an effect on the underlying pathology. In the current study, azelastine had a mild effect on sneezing, but no effect on nasal blockage or rhinorrhea. This minor control of symptoms offered by azelastine is in agreement with a recently published International Consensus Report on the Diagnosis and Management of Rhinitis,1 which recommends the use of antihistamines in patients with mild disease or occasional symptoms. The action of antihistamines contrasts with those of corticosteroids, which have a direct effect on the inflammatory process by decreasing the degree of infil-
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tration of the nasal mucosa by inflammatory cells, especially basophils and eosinophils; reducing airway hyperresponsiveness; and limiting edema and mucus secretion. This has been demonstrated in a study comparing topical preparations of budesonide and levocabastine.11 Consequently, topical corticosteroids are recommended for patients with moderate disease or troublesome nasal symptoms. The number and severity of reported adverse events in this study were similar in both treatment groups. No measurements of possible systemic effects exerted by the drugs were undertaken. A number of clinical studies have investigated the effects of plasma and urinary cortisol induced by budesonide in daily doses of up to 800 g and no difference between nasal budesonide and placebo or baseline have been demonstrated in any of these studies.12–14 The present study also provides evidence for the clinical superiority of nasal budesonide over azelastine. The combined evaluation of efficacy and safety indicates that budesonide has an increased ratio of benefit and risk as compared with azelastine. In conclusion, the results of this study indicate that intranasal budesonide in an aqueous suspension at a once daily dose of 256 g is well tolerated and provides good and clinically important relief of the symptoms of perennial allergic rhinitis. Budesonide
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was significantly more effective than azelastine nasal spray at a dose of 280 g, administered twice daily (560 g/ per day), and placebo. 9.
REFERENCES 1. International Rhinitis Management Working Group. International consensus report on the diagnosis and management of rhinitis. Allergy 1994;19: 1–34. 2. Brogden RN, McTavish D. Budesonide. An updated review of its pharmacological properties and therapeutic efficacy in asthma and rhinitis. Drugs 1992;44:375– 407. 3. Day J, Andersson B. A double-blind comparison of Rhinocort威 (budesonide) Aqua, MDI and placebo in the treatment of seasonal allergic rhinitis. Am J Rhinol 1996;00:000 – 000. 4. McTavish D, Sorkin EM. Azelastine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1989;38: 778 – 800. 5. Simons FER, Simons KJ. Secondgeneration H1-receptor antagonists. Ann Allergy 1991;66:5–16 and 19. 6. Simpson RJ. Budesonide and terfenadine, separately and in combination, in the treatment of hay fever. Ann Allergy 1994;73:497–502. 7. Munch EP, Soborg M, Norreslet TT, Mygind N. A comparative study of dexchlorpheniramine maleate sustained release tablets and budesonide nasal spray in seasonal allergic rhinitis. Allergy 1983;38:517–24. 8. Lau SK, Wei WI, Van Hasselt CA, et al. A clinical comparison of budes-
10.
11.
12.
13.
14.
onide nasal aerosol, terfenadine and a combined therapy of budesonide and oxymatazoline in adult patients with perennial rhinitis. Asian Pac J Allergy Immunol 1990;8:109 –15. Gastpar H, Aurich R, Petzold U, et al. Intranasal treatment of perennial allergic rhinitis. Comparison of azelastine nasal spray and budesonide aerosol. Arzneim-Forsh/Drug Res 1993;43: 475–9. Bunnag C, Jareoncharsri P, Wong EC. A double-blind comparison of nasal budesonide and oral astemizole for the treatment of perennial rhinitis. Allergy 1992;47:313–7. Andersson M, Svensson C, Greiff L, et al. Effects of topical levocabastine and budesonide on nasal responses during a Swedish birch pollen season. Eur Respir J 1995;8(Suppl 19):138. Wight RG, Jones AS, Beckingham E, et al. A double blind comparison of intranasal budesonide 400 g and 800 g in perennial rhinitis. Clin Otolaryngol 1992;17:354 – 8. Pedersen B, Bundgaard Larsen B, Dahl R, et al. Powder administration of pure budesonide for the treatment of seasonal allergic rhinitis. Allergy 1991;46:582–7. Norman PS, Creticos PS, Tobey R, et al. Budesonide in grass pollen rhinitis. Ann Allergy 1992;69:309 –16.
Request for reprints should be addressed to: Mr Erik Lanner, MD Astra Draco Scheeleragen 2 S-223 63 Lund Sweden
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Allergic rhinitis is usually treated with oral antihistamines or nasal steroids. Topically active nasal antihistamine is a new treatment modality for allergic rhinitis. The efficacy in comparison to well established topical treatment alternatives is not fully known. Objective: To compare the efficacy of intranasally administered azelastine to budesonide, at their respectively recommended dosage, on the symptoms of perennial rhinitis patients. Methods: A placebo-controlled, randomized, parallel group study was conducted to compare the efficacy and tolerability of intranasal budesonide aqueous suspension (256 g once daily) with azelastine hydrochloride nasal spray (280 g twice daily (560 g/day)) and with placebo in the treatment of perennial allergic rhinitis. The 195 patients (with at least a 2-year history of perennial allergic rhinitis) recorded individual nasal symptom scores, the degree of symptom control achieved and any adverse events experienced over a 2-week baseline period and a 6-week treatment period. Results: Following treatment, the reductions in mean combined and individual nasal symptom scores from baseline values were significantly greater in the budesonide group compared with the placebo group (P ⬍ .0001 for all variables except runny nose P ⫽ .01). In patients treated with budesonide, there were also significantly larger reductions from baseline values in combined nasal symptom scores (P ⬍ .01) and in scores for all individual nasal symptoms (P ⱕ .05) compared with those treated with azelastine. The reductions from baseline in both combined and individual nasal symptom scores did not differ between azelastine and placebo. The study medications were well tolerated, producing no unexpected or serious treatment-related adverse events. Conclusion: A once-daily dose of 256 g of intranasal budesonide aqueous suspension is significantly more effective at relieving the symptoms of perennial allergic rhinitis compared with a twice daily dose of 280 g of azelastine nasal spray. Ann Allergy Asthma Immunol 1998;81:354–358.
INTRODUCTION Perennial allergic rhinitis is characterized by nasal obstruction, rhinorrhea, sneezing, and nasal itching. The aller* Martin A. Stern, MD, Midlands Asthma and Allergy Research Association (MAARA), Leicester General Hospital, Leicester, United Kingdom. This study was supported by a grant from Astra Draco AB, Lund, Sweden. Received for publication October 17, 1997. Accepted for publication in revised form March 24, 1998.
354
gens responsible are perennial (such as house dust mites and animal dander) and are often ubiquitous and, therefore, unavoidable. The first line of treatment is with oral antihistamines if the symptoms are mild. If the symptoms are more troublesome, topical treatment is recommended with nasal sprays or aqueous suspensions containing corticosteroids, such as budesonide. Supplementation on an ‘as needed’ basis can be provided with an oral antihistamine.1
Nasal inhalation of topically active budesonide has been shown to be effective and safe in the treatment of both perennial and seasonal allergic rhinitis.2 Delivery of budesonide from a nasal pressurized metered dose inhaler has been shown to result in retention of a proportion of the nominal dose in the nasal adapter: for example, 256 g of a nominal dose of 400 g is delivered to the patient from a nasal pressurized metered dose inhaler whereas the entire nominal dose (400 g) is delivered with an aqueous nasal spray. A recent study comparing a dose of 256 g with a dose of 400 g of budesonide aqueous suspension, each given once daily, has shown that the lower dose has a similar clinical efficacy to that of the higher dose.3 Azelastine is a second-generation histamine H1-receptor antagonist which also inhibits the release of other mediators involved in the pathogenesis of allergic disease and bronchial asthma.4,5 Azelastine (280 g twice daily) administered intranasally was found in open and uncontrolled studies to have similar efficacy to intranasal budesonide (100 g twice daily) for the treatment of patients with perennial allergic rhinitis.6 The aim of the current placebo-controlled study was to compare the efficacy of budesonide (256 g once daily) and azelastine (280 g twice daily) aqueous nasal sprays, and placebo in the treatment of patients with perennial allergic rhinitis. The primary efficacy variables were daily nasal symptom scores, evaluated from patient diaries, and the patients’ overall assessment of treatment efficacy.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
METHODS Subjects A total of 195 adult patients with at least a 2-year history of perennial allergic rhinitis, confirmed by a positive skin prick test, were recruited into the study at four centres in the UK. Preferably, patients were allergic to house dust mites, although patients allergic to cat, dog, Alternaria and Cladosporium were also accepted. In addition, the patients had to demonstrate at least one of the nasal symptoms of blocked nose, rhinorrhea, or sneezing with scores higher than or equal to 2 (moderate symptoms) on a 0 to 3 point scale on four or more days of the 2-week baseline period. Patients with septal deviation or other anatomic nasal obstructions that would prevent the effective penetration of the nasal spray were not enrolled in the trial. In addition, patients who had used topical nasal corticosteroid therapy in the previous 2 weeks, oral systemic corticosteroid therapy in the preceding 2 months, depot steroid therapy in the previous 6 months or immunotherapy for perennial allergic rhinitis in the past 2 years did not participate in the study. Pregnant women and nursing mothers were also excluded. The study was performed in accordance with the principles of the declaration of Helsinki. The protocol was approved by a regional ethics committee and signed informed consent was obtained from all patients. The study was sponsored by Astra Draco AB, Sweden. Study Design The study was a multicenter, placebocontrolled, randomized, parallel group trial and was double-blind with respect to budesonide and placebo, and investigator-blind with respect to azelastine. This was achieved by having a third person at the clinic handle all communication regarding the drugs with the patient. The patients were informed that some patients will get budesonide, some will get azelastine, and the rest will get sprays containing a dummy treatment (placebo). After a 2-week baseline period, the patients were ran-
VOLUME 81, OCTOBER, 1998
domized in a computerized scheme in balanced blocks of three to one of the treatment groups budesonide aqueous suspension (256 g once daily), azelastine aqueous suspension (280 g twice daily), or placebo (once daily) for a period of 6 weeks. Terfenadine tablets (60 mg) were used as rescue medication, if needed. Clinical Efficacy Symptom evaluation was achieved through a score system recorded in diaries. Every evening, patients assessed the severity of the individual symptoms (blocked nose, rhinorrhea, and sneezing) according to a 4-point scale: 0 ⫽ no symptoms, 1 ⫽ mild symptoms (not troublesome), 2 ⫽ moderate symptoms (troublesome, but not enough to interfere with normal daily activity or sleep), and 3 ⫽ severe symptoms (interfere with normal activity or sleep). Combined symptom scores were the sum of the scores for the three individual nasal symptoms. The mean patient scores of both individual and combined symptom severity were calculated for the 2-week baseline period and for the 6-week treatment period. In addition, patients made an overall assessment of treatment efficacy after 6 weeks of treatment according to the degree of symptom control achieved (aggravation, none, minor, substantial, or total control). The number of terfenadine tablets taken as rescue medication (a maximum of two tablets per day) was also recorded. Tolerability The incidence, severity, and nature of adverse events were determined by examining and questioning the patients after 3 and 6 weeks of treatment. A rhinoscopic examination was also performed at each visit including an evaluation of hypertrophy of the conchae, nasal polyps, pus, secretion, other structural defects or any signs of candida infection. Statistical Analysis A sample size of 50 patients in each treatment group was estimated to provide an 80% power to detect a treat-
ment difference of 0.40 in the individual symptom scores, assuming a standard deviation of 0.7. The mean symptom scores for the 2-week baseline period and the 6-week treatment period and the differences between these scores were calculated for each of the three treatment groups. The differences in individual symptom scores and mean combined nasal symptom scores between the baseline and treatment periods were based on all patients treated approach and subjected to an analysis of variance, with treatment and center as factors included in the model. Overall assessment of treatment efficacy and the difference in terfenadine use between baseline and treatment periods were also subjected to an analysis of variance. The main analysis of clinical efficacy was based on the all patients treated approach: all patients who had taken at least one dose of the study medication were included. RESULTS Patient Population A total of 195 patients (65 in each treatment group) completed the baseline assessment and entered the treatment period (Table 1). Fifty patients discontinued the study during the treatment period because of adverse events (n ⫽ 17; placebo 4, azelastine 7, budesonide 6), disease deterioration (n ⫽ 14; placebo 7, azelastine 3, budesonide 4) or other reasons (n ⫽ 19; placebo 5, azelastine 9, budesonide 5). Consequently, 145 patients completed the entire trial. The three treatment groups were comparable with respect to sex, age, weight, height, and disease duration. The majority of patients were allergic to house mites with an even distribution between the treatment groups (Table 2). The mean disease duration was 13.4 years (range: 2 to 45 years). During the baseline period, the means of the combined nasal symptom scores in the three treatment groups were 4.28 for placebo, 3.85 for azelastine, and 4.33 for the budesonide group. The individual means of the symptom scores for blocked nose were
355
1.7, 1.5, and 1.6 in the placebo, azelastine and budesonide groups. For rhinorrhea the corresponding values were 1.3, 1.3, and 1.4. For sneezing the values were 1.2, 1.1, and 1.3. Clinical Efficacy A comparison of the reductions in mean combined and individual nasal symptom scores (blocked nose, rhinorrhea, and sneezing) from baseline values showed that this reduction was significantly greater in the budesonide group compared with the placebo group. There were also significantly larger changes from baseline values in combined nasal symptom scores and in individual nasal symptom scores in the budesonide group compared with the azelastine treatment group. In contrast, azelastine did not produce a significant improvement in either combined or individual nasal symptoms during the 6-week treatment period compared with placebo (Fig 1). The patients’ overall assessments of treatment efficacy after 6 weeks of therapy indicated that budesonide produced significantly superior symptom control compared with both azelastine and placebo (P ⫽ .013 and P ⫽ .0003, respectively (Fig 2). In addition, at the end of the 6-week treatment period, there was no significant difference between azelastine and placebo with respect to the degree of symptom control achieved (P ⫽ .20). A secondary efficacy variable was the use of terfenadine tablets (60 mg) as rescue medication during the baseline and treatment periods. The reduction from baseline in the weekly consumption of terfenadine was significantly greater for budesonide (⫺1.03 tablets, P ⫽ .0033) and azelastine (⫺1.61 tablets, P ⫽ .0015) compared with placebo (⫹0.06 tablets), but there were no differences between the two active treatments (P ⫽ .80; Table 3). Tolerability No unexpected or treatment-related adverse events were reported; however, 17 of the 195 patients enrolled in the study discontinued the trial because of adverse events (six in the budesonide
356
Table 1. Demographic Characteristics of Patients Entering the 6-Week Treatment Period Treatment Group
Number of patients Age, years Mean Range Gender Male/female Disease duration, yr Mean Range
Placebo
Azelastine, 280 g, bid
Budesonide, 256 g, qd
All
65
65
65
195
35.3 18–60
38.2 18–73
37.2 19–68
36.9 18–73
33/32
33/32
33/32
99/96
11.8 2–39
13.5 2–45
14.8 2–40
13.4 2–45
qd ⫽ once daily and bid ⫽ twice daily. Table 2. Distribution of Different Allergens Between Treatment Groups (%) Allergen D. pteronyssinus D. farinae Dog Cat Alternaria Cladosporium
Placebo, %
Azelastine, %
Budesonide, %
Total, %
29.7 24.6 16.4 19.0 6.2 4.6
29.2 23.1 14.4 13.9 5.6 3.6
31.8 21.5 16.4 18.0 6.7 5.0
90 69 47 51 18 13
group, seven in the azelastine group and four in the placebo group). The majority of adverse events were of mild or moderate intensity and were similar between the three treatment groups. The most frequently reported adverse events were respiratory infection, headache, flu-like disorders, and epistaxis. One serious adverse event (hepatic cirrhosis) was reported in the placebo group but any causal relationship to the study medication was considered unlikely. Rhinoscopic examinations did not reveal any major abnormalities, and there were no cases of Candida infection. A clear tendency of change towards none or mild for mucosal swelling and secretion was seen in the budesonide group as compared with the other two treatment groups. DISCUSSION The present study has shown that intranasal budesonide aqueous suspension (256 g once daily) is significantly more efficacious than both placebo and azelastine nasal spray (280 g twice daily) in controlling the symptoms of perennial allergic rhini-
tis. This difference in activity between budesonide and azelastine also appeared to be clinically relevant since 70% of patients treated with budesonide reported substantial or total control over symptoms compared with only 45% and 27% of patients treated with azelastine and placebo, respectively. The distribution and severity of the individual symptoms were similar in the treatment groups. The higher consumption of rescue medication in the azelastine group might have reduced the symptom scores during baseline to a greater extent than in the budesonide treated group. The higher consumption could reflect that the azelastine group was more symptomatic and, thus, would have had more improvement to gain as a result of treatment. In the comparison the gain in the budesonide treated group was greater. Of the individual nasal symptoms, nasal blockage is the most troublesome in patients with perennial allergic rhinitis. It is, therefore, of particular interest that budesonide produced twice as large a decrease in the score for blocked nose than did azelastine.
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Figure 1. Change of individual and combined mean nasal symptom scores from baseline (AZEL ⫽ azelastine treated group, BUD ⫽ budesonide treated group).
Figure 2. Patients overall assessment of efficacy after 6 weeks of treatment. (AZEL ⫽ azelastine treated group, and BUD ⫽ budesonide treated group).
Several double-blind studies, comparing nasal budesonide with various antihistamines, in both seasonal and perennial allergic rhinitis have demonstrated budesonide to be superior.6 – 8 In contrast, a previous open trial showed that azelastine nasal spray (280 g twice daily) was more effective than a low dose of budesonide nasal pressurized metered dose inhaler (100 g twice daily) in controlling the symptoms of perennial allergic rhinitis.9 In a double-blind study, however, nasal
Table 3. Mean Weekly Consumption of As-Needed Terfenadine Tablets (60 mg) during Baseline and Treatment Periods Treatment Period
Baseline period Treatment period Difference
Placebo
Azelastine, 280 g, bid
Budesonide, 256 g, qd
2.14 2.20 ⫹0.06
2.66 1.05 ⫺1.61
1.67 0.64 ⫺1.03
VOLUME 81, OCTOBER, 1998
budesonide was demonstrated as being more efficient than astemizole given orally, in controlling the symptoms of perennial rhinitis.10 As stated in a consensus report, antihistamines have usually been taken orally (either as tablets or syrup), which has the advantage of reducing systemic symptoms such as conjunctivitis and urticaria. Unfortunately, some serious cardiac side effects have been observed with some antihistamines taken orally, but these side-effects are not due to class-effect of antihistamines. Topical antihistamines such as azelastine and levocabastine can be used for acute symptomatic relief and prophylaxis of allergic rhinitis without any systemic side effects.1 The current study was single-blind, rather than double-blind with respect to azelastine since no azelastine-placebo was available. The investigator was thereby kept unaware of the study treatment and could not influence the assessment of treatment efficacy made by the patients. Azelastine is a topical second-generation H1-receptor antagonist that has properties similar to terfenadine, loratadine, and cetirizine: it is effective at inhibiting the release of histamine and prostaglandin from mast cells and basophils. Perennial allergic rhinitis is characterized by a chronic inflammatory reaction in the nasal epithelium and submucosa involving mast cells, eosinophils, T cells, and macrophages. Although antihistamines may help to alleviate symptoms, it is doubtful to what extent they exert an effect on the underlying pathology. In the current study, azelastine had a mild effect on sneezing, but no effect on nasal blockage or rhinorrhea. This minor control of symptoms offered by azelastine is in agreement with a recently published International Consensus Report on the Diagnosis and Management of Rhinitis,1 which recommends the use of antihistamines in patients with mild disease or occasional symptoms. The action of antihistamines contrasts with those of corticosteroids, which have a direct effect on the inflammatory process by decreasing the degree of infil-
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tration of the nasal mucosa by inflammatory cells, especially basophils and eosinophils; reducing airway hyperresponsiveness; and limiting edema and mucus secretion. This has been demonstrated in a study comparing topical preparations of budesonide and levocabastine.11 Consequently, topical corticosteroids are recommended for patients with moderate disease or troublesome nasal symptoms. The number and severity of reported adverse events in this study were similar in both treatment groups. No measurements of possible systemic effects exerted by the drugs were undertaken. A number of clinical studies have investigated the effects of plasma and urinary cortisol induced by budesonide in daily doses of up to 800 g and no difference between nasal budesonide and placebo or baseline have been demonstrated in any of these studies.12–14 The present study also provides evidence for the clinical superiority of nasal budesonide over azelastine. The combined evaluation of efficacy and safety indicates that budesonide has an increased ratio of benefit and risk as compared with azelastine. In conclusion, the results of this study indicate that intranasal budesonide in an aqueous suspension at a once daily dose of 256 g is well tolerated and provides good and clinically important relief of the symptoms of perennial allergic rhinitis. Budesonide
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was significantly more effective than azelastine nasal spray at a dose of 280 g, administered twice daily (560 g/ per day), and placebo. 9.
REFERENCES 1. International Rhinitis Management Working Group. International consensus report on the diagnosis and management of rhinitis. Allergy 1994;19: 1–34. 2. Brogden RN, McTavish D. Budesonide. An updated review of its pharmacological properties and therapeutic efficacy in asthma and rhinitis. Drugs 1992;44:375– 407. 3. Day J, Andersson B. A double-blind comparison of Rhinocort威 (budesonide) Aqua, MDI and placebo in the treatment of seasonal allergic rhinitis. Am J Rhinol 1996;00:000 – 000. 4. McTavish D, Sorkin EM. Azelastine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1989;38: 778 – 800. 5. Simons FER, Simons KJ. Secondgeneration H1-receptor antagonists. Ann Allergy 1991;66:5–16 and 19. 6. Simpson RJ. Budesonide and terfenadine, separately and in combination, in the treatment of hay fever. Ann Allergy 1994;73:497–502. 7. Munch EP, Soborg M, Norreslet TT, Mygind N. A comparative study of dexchlorpheniramine maleate sustained release tablets and budesonide nasal spray in seasonal allergic rhinitis. Allergy 1983;38:517–24. 8. Lau SK, Wei WI, Van Hasselt CA, et al. A clinical comparison of budes-
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onide nasal aerosol, terfenadine and a combined therapy of budesonide and oxymatazoline in adult patients with perennial rhinitis. Asian Pac J Allergy Immunol 1990;8:109 –15. Gastpar H, Aurich R, Petzold U, et al. Intranasal treatment of perennial allergic rhinitis. Comparison of azelastine nasal spray and budesonide aerosol. Arzneim-Forsh/Drug Res 1993;43: 475–9. Bunnag C, Jareoncharsri P, Wong EC. A double-blind comparison of nasal budesonide and oral astemizole for the treatment of perennial rhinitis. Allergy 1992;47:313–7. Andersson M, Svensson C, Greiff L, et al. Effects of topical levocabastine and budesonide on nasal responses during a Swedish birch pollen season. Eur Respir J 1995;8(Suppl 19):138. Wight RG, Jones AS, Beckingham E, et al. A double blind comparison of intranasal budesonide 400 g and 800 g in perennial rhinitis. Clin Otolaryngol 1992;17:354 – 8. Pedersen B, Bundgaard Larsen B, Dahl R, et al. Powder administration of pure budesonide for the treatment of seasonal allergic rhinitis. Allergy 1991;46:582–7. Norman PS, Creticos PS, Tobey R, et al. Budesonide in grass pollen rhinitis. Ann Allergy 1992;69:309 –16.
Request for reprints should be addressed to: Mr Erik Lanner, MD Astra Draco Scheeleragen 2 S-223 63 Lund Sweden
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